Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[N:4]([CH3:21])[C:3]1=[O:22].C(N(S(F)(F)[F:29])CC)C>C(Cl)Cl>[F:29][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[N:4]([CH3:21])[C:3]1=[O:22]
Reactant: CCN(CC)S(F)(F)F
Reactant: CN1C(=O)C(O)N=C(c2ccccc2F)c2cc(Cl)ccc21
Solvent: ClCCl
Product: CN1C(=O)C(F)N=C(c2ccccc2F)c2cc(Cl)ccc21
Temperature: 0 °C

Procedure:
A solution of 1.4 g of 3-hydroxy-1,3-dihydro-1-methyl-7-chloro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one in 10 ml of methylene chloride was added dropwise to a stirred solution of 1.5 ml of diethylaminosulfur trifluoride in 50 ml methylene chloride cooled to -70°. The reaction mixture was allowed to warm slowly to 5° and then poured into 100 ml of ice water. The lower organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. The residue was recrystallized from heptane to give 1.17 g of 3-fluoro-1,3-dihydro-1-methyl-7-chloro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one as cream-colored crystals: mp 91°-95°; Hu 1H nmr (CCl3D) δ 3.51 ppm (s, 3H), 5.66 ppm (d, J = 57 Hz, 1H) and 7.5 ppm (m, 7H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C:15]1=[O:20].[CH3:21][C:22]1[C:30]2[CH2:29][O:28][C:27](=[O:31])[C:26]=2[CH:25]=[CH:24][C:23]=1[C@@H:32]1[CH2:34][O:33]1>CCO>[OH:33][C@H:32]([C:23]1[CH:24]=[CH:25][C:26]2[C:27](=[O:31])[O:28][CH2:29][C:30]=2[C:22]=1[CH3:21])[CH2:34][N:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:11])[O:8][CH2:9][C:10]=3[C:2]=2[CH3:1])[C:15](=[O:20])[CH2:16]1
Reactant: Cc1c(CCN2CCNCC2=O)ccc2c1COC2=O
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c(CCN2CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)CC2=O)ccc2c1COC2=O
Temperature: 100 °C

Procedure:
A sealed tube containing 1-[2-(4-Methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-2-one (60 mg, 0.19 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one dissolved in 1 mL of EtOH was heated to 100° C. overnight. After 16 hrs the solvent was removed and the material purified via flash chromatography to give the title product. LC-MS (IE, m/z): 465 [M+1]+.
Reaction SMILES: [C:1]([CH2:23][OH:24])([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([F:22])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[CH2:25](Br)[CH:26]=[CH2:27].[OH-].[K+]>CS(C)=O.O>[C:1]([CH2:23][O:24][CH2:27][CH:26]=[CH2:25])([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([F:20])([F:21])[F:22])([F:17])[F:18])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=CCOCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 4 h
Yield: 75.5 %

Procedure:
To a stirred solution of 124 g of C7F15CH2OH and 62 g of allyl bromide in 1240 g of dimethyl sulfoxide was dropwise added a solution of 28.1 g of potassium hydroxide in 35 g of water. The mixture was allowed to stir for 4 hr, during which time it separated into two immiscible liquid phases. The reaction mixture was poured into a separatory funnel, and the lower layer was isolated and washed 3 times with water to remove any remaining solvent. The crude product was dried over anhydrous magnesium sulfate, filtered, and vacuum distilled to yield 103 g of C7F15CH2OCH2CH═CH2 (E1), b.p. 88-89° C. at 30 torr (4 kilopascals (kPa)).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].C([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(OC(C)(C)C)=O.[ClH:32]>O1CCOCC1>[ClH:32].[CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:18])=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:8])([F:9])[F:10]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(C(=O)N3CCNCC3)s2)noc1C(F)(F)F
Reaction time: 12 h
Yield: 69 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and N-Boc-piperazine by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried then chromatographed on silica gel with EtOAc/hexanes (50%) as eluant to afford intermediate N-Boc protected product as a colorless solid (165 mg, 74%). The Boc-protected intermediate was dissolved in 1,4-dioxane (5 mL) and treated with a 4 N solution of hydrogen chloride in 1,4-dioxane and stirred for 12 hr, after which time the reaction mixture was evaporated to approximately ½ volume and diluted with ethyl ether (20 mL). The resulting solids were filtered and air dried to afford product as a colorless solid (131 mg, 69% overall). 1H NMR (D2O) 2.16 (s, 3 H), 3.22 (m, 4 H), 3.87 (m, 4 H), 7.34 (d, J=4.0, 1 H), 7.42 (d, J=4.0, 1 H). 19F NMR −63.6. LC/MS 4.34 min, [M+1]+ 346.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:14][C:15](=[O:42])[N:16]([CH:18]1[CH2:23][CH2:22][CH:21]([NH:24][CH2:25][C:26]2[CH:27]=[C:28]([C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=3)[C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:20][CH2:19]1)[CH3:17])([CH3:13])([CH3:12])[CH3:11].[Cl:43][C:44]1[C:45]2[CH:55]=[CH:54][CH:53]=[CH:52][C:46]=2[S:47][C:48]=1[C:49](Cl)=[O:50]>ClCCl>[C:10]([O:14][C:15](=[O:42])[N:16]([CH:18]1[CH2:23][CH2:22][CH:21]([N:24]([C:49]([C:48]2[S:47][C:46]3[CH:52]=[CH:53][CH:54]=[CH:55][C:45]=3[C:44]=2[Cl:43])=[O:50])[CH2:25][C:26]2[CH:27]=[C:28]([C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=3)[C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:20][CH2:19]1)[CH3:17])([CH3:13])([CH3:11])[CH3:12]
Reactant: COc1ccc(CNC2CCC(N(C)C(=O)OC(C)(C)C)CC2)cc1-c1ccc(C#N)cc1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)c2sc3ccccc3c2Cl)C2CCC(N(C)C(=O)OC(C)(C)C)CC2)cc1-c1ccc(C#N)cc1
Yield: 92.8 %

Procedure:
N,N-Diisopropylethylamine (2.1 mL, 12.1 mmol) was added to a solution of amine 5 (2.2 g, 4.9 mmol), 3-chlorobenzo[b]thiophene-2-carbonyl chloride (1.3 g, 5.86 mmol) and anhydrous dichloromethane (22 mL), with stirring under argon. Once all of the starting material had been consumed as monitored by TLC (˜2.5 hours), the mixture was washed with water, saturated aqueous sodium hydrogen carbonate, and brine. The organic layer was dried (MgSO4), and concentrated in vacuo. The yellow residue was then purified by silica-gel chromatography using hexane/ethyl acetate 3:1 to give the title compound 6 (2.93 g, 93%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[N:12]=[C:13](Br)[C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[CH:16]=1.C(OCC)(=O)C>CN(C=O)C>[Br:10][C:11]1[N:12]=[C:13]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[CH:16]=1
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: N#Cc1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Nc2nc(Br)cn3ccnc23)cc1
Temperature: 140 °C

Procedure:
A mixture of 4-aminobenzonitrile (220 mg; 1.89 mmol) and 6,8-dibromo-imidazo[1,2-a]pyrazine (500 mg; 1.81 mmol) is slurried in DMF (1 mL) and heated to 140° C. for 20 minutes. The reaction is allowed to cool, and when the bath reaches 75° C., ethyl acetate (40 mL) is added and the slurry is stirred to break up large solid lumps into fine powder. The powdered 4-(6-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzonitrile is filtered, washed with diethyl ether (2×50 mL) and dried under vacuum to a fine orange/tan solid (600 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[S:28])[CH:22]=[C:23]([Cl:25])[CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27](=[S:28])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[F:17])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: Nc1cc(C(=O)Nc2ccccc2)ccc1F
Product: O=C(Nc1ccccc1)c1ccc(F)c(NC(=S)Nc2cc(Cl)cc(Cl)c2)c1
Yield: 49.6 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-fluoro-N-phenyl-benzamide from Example 9 (0.481 g, 2.09 mmol) and 3,5-dichlorophenyl isothiocyanate (0.427 g, 2.09 mmol). Filtration afforded the product (0.45 g) in two crops; m.p. 173-175° C.
Reaction SMILES: [F:1][C:2]1([CH3:19])[C@@:6]([OH:8])([CH3:7])[CH:5]([CH2:9][OH:10])[O:4][C@H:3]1[N:11]1[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]1=[O:18].[C:20](Cl)(=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24].O>ClCCl>[C:20]([O:10][CH2:9][C@@H:5]1[C:6]([OH:8])([CH3:7])[C@:2]([F:1])([CH3:19])[CH:3]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[O:4]1)(=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCC(=O)Cl
Reactant: CC1(F)[C@H](n2ccc(=O)[nH]c2=O)OC(CO)[C@@]1(C)O
Solvent: ClCCl
Solvent: O
Product: CCCCC(=O)OC[C@H]1OC(n2ccc(=O)[nH]c2=O)[C@](C)(F)C1(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a solution of 1-((2R,4R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3,4-dimethyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (about 0.30 g, 1.09 mmol) in dichloromethane (about 5 ml) was added a solution of valeroylchloride (about 0.33 ml, 2.70 mmol) in dichloromethane (about 5 ml) at about 0° C. and stirred at room temperature for overnight. Completion of the reaction monitored by thin-layer chromatography, water added to the reaction mixture and extracted with dichloromethane and the combined organic layers were washed with saturated sodium bicarbonate, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 2% methanol in dichloromethane to elude title compound (0.10 g) as a colorless solid. Yield: 27%; 1H NMR (300 MHz, CDCl3): δ 8.31 (bs, 1H), 7.39-7.35 (dd, 1H, J1=8.1 Hz, J2=8.4 Hz), 6.36 (d, 1H, J=22.5 Hz), 5.76-5.72 (dd, 1H, J1=8.1 Hz, J2=8.4 Hz), 4.58-4.52 (m, 1H), 4.40-4.36 (m, 1H), 4.26-4.20 (m, 1H), 2.64 (s, 1H), 2.40-2.35 (t, 2H), 1.65-1.59 (m, 2H), 1.44 (d, 3H, J=23.1 Hz), 1.37-1.25 (m, 5H), 0.95-0.90 (t, 3H); ES Mass: [M+Na]+: 381 (100%), [M+1]+ 359 (40%); IR cm−: 3504, 3145, 1710, 1676, 1560, 1265, 1180, 1039, 938, 824; HPLC: 99%.
Reaction SMILES: [F:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][OH:4].N1C=CC=CC=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>O>[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([O:4][CH2:3][CH:2]([F:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CCCCCCCCC(F)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 72.2 %

Procedure:
17 g of 2-fluorodecanol and 60 ml of pyridine were charged into a 300 ml three-necked round bottom flask and cooled to 0° C. to which 24 g of p-toluenesulfonyl chloride was added in 15 min. The system was held at 0° C. for 1 hour and then subjected to reaction for 7 hours while being held below 20° C. Then, the mixture was charged into water and acidified with hydrochloric acid, followed by extraction with dichloromethane. The organic layer was washed with water, dried with magnesium sulfate and then purified by silica gel chromatography with the use of dichloromethane as the eluent to obtain 23 g of 2-fluorodecyl p-toluenesulfonate.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:13])[CH:8]=2)[N:3]=1.[CH:14]1([C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH2:16][CH2:15]1>C(O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:22][C:19]2[NH:20][N:21]=[C:17]([CH:14]3[CH2:16][CH2:15]3)[CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:13])[CH:8]=2)[N:3]=1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: Clc1nc(Cl)c2cc(I)ccc2n1
Solvent: CCO
Product: Clc1nc(Nc2cc(C3CC3)n[nH]2)c2cc(I)ccc2n1
Reaction time: 4 h
Yield: 80.7 %

Procedure:
To a suspension of 2,4-Dichloro-6-iodo-quinazoline (3.14 g, 9.66 mmol) in ethanol (200 mL) was added 5-Cyclopropyl-2H-pyrazol-3-ylamine (2.14 g, 19.3 mmol) in ethanol (50 mL) and the partial solution was stirred for 4 h. Filtration afforded (2-Chloro-6-iodo-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (3.21 g, 81% yield). HNMR (500 MHz, dmso) δ 12.39 (1H, bs), 10.97 (1H, s), 9.15 (1H, s), 8.13 (1H, d), 7.45 (1H, d0, 1.99-1.90 91H, m), 0.99-0.90 (2H, m), 0.80-0.70 (2H, m).
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](Cl)=[O:35])=[CH:29][CH:28]=1)#[N:26]>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:34](=[O:35])[CH2:33][C:30]4[CH:31]=[CH:32][C:27]([C:25]#[N:26])=[CH:28][CH:29]=4)[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(CC(=O)Cl)cc1
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN1CCC(OC(=O)Cc2ccc(C#N)cc2)N(c2nnc(C3CC3)s2)C1=O

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. α-(4-Cyanophenyl)acetyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-[α-(4-cyanophenyl)acetyloxy]-2(1H)-pyrimidinone as the residue.
Reaction SMILES: C(O[C:4]([SH:6])=[S:5])C.[K].Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[NH2:19].Cl>CN(C)C=O>[SH:6][C:4]1[S:5][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:11][C:10]=2[N:19]=1
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Reactant: CCOC(=S)S
Agent: Cl
Agent: [K]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2sc(S)nc2c1
Temperature: 25 °C
Yield: 92 %

Procedure:
In analogy to the procedure of Chaudhuri, N. Synth. Commun. 1996, 26, 20, 3783, O-ethylxanthic acid, potassium salt (Lancaster, 7.5 g, 46.9 mmol) was added to a solution of 2-bromo-5-trifluoromethylphenylamine (Aldrich, 5.0 g, 20.8 mmol) in N,N-dimethylformamide (DMF, 30 mL). The mixture was heated to reflux for 4 hours. After cooling to room temperature, the mixture was poured into ice water and acidified with 2N HCl. The solid product was collected by filtration. Recrystallization from CHCl3/Hexanes gave 239 (4.5 g, 92%) as a white solid.
Reaction SMILES: [C:1](#[N:5])[CH2:2][CH2:3][CH3:4].[CH2:6]([OH:8])[CH3:7].[ClH:9]>C(OC(C)C)(C)C>[ClH:9].[C:1](=[NH:5])([O:8][CH2:6][CH3:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC#N
Reactant: CCO
Agent: Cl
Solvent: CC(C)OC(C)C
Product: CCCC(=N)OCC
Temperature: -20 °C
Reaction time: 96 h

Procedure:
Butyronitrile (85 ml, 839 mmol) is dissolved in absolute ethanol (65 ml, 961 mmol) and cooled to 0° C. to 5° C. While cooling further, gaseous hydrogen chloride (about 40 g, about 1.1 mol, differential weighing of the pressure cylinder) is passed into the solution. The reaction mixture is left at about 4° C. for 96 hours and then, while stirring, 260 ml of diisopropyl ether are added, and the mixture is cooled to −20° C. and filtered with suction at 0° C. through a sintered funnel. The crystals are rapidly (the product is hygroscopic) washed twice with 50 ml of cold diisopropyl ether each time and stored, sealed air-tight, in a refrigerator.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.C(N(CC)CC)C.P(Cl)(Cl)([Cl:22])=O>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[Cl:22]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ccc(Br)cc12
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Clc1ncnc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 6-Bromo-3H-quinazolin-4-one (1.5 g, 6.65 mmole) in 1,4-dioxane (30 ml) under nitrogen was added triethylamine (2.8 ml, 19.9 mmole). The resulting suspension was rapidly stirred while phosphorous oxychloride (1.85 ml, 19.9 mmole) was added over 5 minutes. The reaction was stirred at room temperature for 5 minutes, then heated at 80° C. for 30 minutes, when no starting material was detectable by LC/MS. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The resulting residue was partitioned between ethyl acetate and water. The insoluble material was collected by filtration and washed with water. The layers of the filtrate where separated and the organic layer was washed twice with water and once with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The resulting solid was combined with the collected precipitate and the mixture was recrystallized from ethyl acetate/hexanes to give 760 mg after drying in vacuo. The resulting compound was characterized as follows: masspectrometry: M/Z=244; HPLC: method A, Rt 1.51 minutes.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.C(#N)C.[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([S:35]([C:38]1[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=1)(=[O:37])=[O:36])[C:30]([Sn](C)(C)C)=[CH:29]2>C(Cl)(Cl)Cl>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([S:35]([C:38]1[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=1)(=[O:37])=[O:36])[C:30]([F:21])=[CH:29]2
Reactant: Cc1ccc(S(=O)(=O)n2c([Sn](C)(C)C)cc3cc(Cl)ccc32)cc1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2c(F)cc3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.7 %

Procedure:
N-fluoro-N′-(chloromethyl)triethylenediamine bis(tetrafluoroborate) (2.33 g) was added to an acetonitrile solution (88 ml) containing 5-chloro-1-tosyl-2-(trimethylstannyl)-1H-indole (2.05 g) obtained in the 2nd step in a nitrogen atmosphere, followed by stirring at room temperature for 16 hours. Chloroform was added to the reaction solution, an insoluble precipitate was removed, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=0:1 to 1:100), and a light yellow solid of 5-chloro-2-fluoro-1-tosyl-1H-indole (520 mg) was thus obtained.
Reaction SMILES: C([O:4][C@H:5]1[C:9](=[CH2:10])[O:8][C@H:7]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:6]1)(=O)C.N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>N.CO>[Si:25]([O:4][C@H:5]1[C:9](=[CH2:10])[O:8][C@H:7]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:6]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C1O[C@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1OC(C)=O
Agent: N
Agent: c1c[nH]cn1
Solvent: CO
Product: C=C1O[C@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 11 h
Yield: 97.3 %

Procedure:
Compound 8 (5.2 g, 19.53 mmol) in saturated NH3 in MeOH (150 mL) was kept at room temperature for 9 h. After evaporation, the residue was dissolved in DMF (60 mL). To this were added imidazole (5.32 g, 78.12 mmol) and tert-butyldimethylsilyl chloride (8.83 g, 58.59 mmol) at 0° C. The reaction mixture was stirred at room temperature for 11 h, and then partitioned between EtOAc/H2O (250 mL/50 mL×4). Silica gel column chromatography (hexane/EtOAc=10/1) of the organic layer gave 9 (6.43 g, 97%) as a foam: UV (MeOH) λmax 266 nm (ε11600), λmin 236 nm (ε5700); 1H NMR (CDCl3) δ 0.11 and 0.14 (6H, each as s, SiMe), 0.88 (9H, s, SiBu-t), 1.92 (3H, d, J6,CH3=1.2 Hz, Me), 2.03 (1H, dt, Jgem=10.8 Hz, J1′,2′a=3.2 Hz and J2′a,3′=3.2 Hz, H-2′a), 2.61-2.68 (1H, m, H-2′b), 4.25 (1H, d, Jgem=2.2 Hz, H-5′a), 4.57 (1H, d, Jgem=2.2 Hz, H-5′b), 4.68 (1H, dd, J2′a,3′=3.2 Hz, J2′b,3′=6.8 Hz H-3′), 6.46 (1H, dd, J1′,2′a=3.2 Hz and J1′,2′b=7.2 Hz, H-1′), 7.44 (1H, d, J6,CH3=1.2 Hz, H-6), 9.12 (1H, br, NH); FAB-MS m/z 339(M++H). Anal. Calcd for C16H26N2O4Si: C, 56.78; H, 7.74; N, 8.28. Found: C, 56.61; H, 7.87; N, 8.17.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:6][C:3]=1[CH:4]=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][C:25]#[N:26]>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]1[C:25]([NH2:26])=[N:1][C:2]2[C:3]([CH:4]=1)=[CH:6][C:7]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:8][CH:9]=2
Reactant: COCCOc1ccc(N)c(C=O)c1
Reactant: COc1ccccc1CCC#N
Product: COCCOc1ccc2nc(N)c(Cc3ccccc3OC)cc2c1

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-5-(2-methoxy-ethoxy)benzaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CS[C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[N:23][C:21]=2[N:22]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[N:23][C:21]=2[N:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Reactant: CSc1nc2ncccc2o1
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1nc2ncccc2o1

Procedure:
The title compound (0.7 g) was prepared from (RS)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.64 g) and 2-methylthio-4-azabenzoxazole Chu-Moyer et al J. Org. Chem. (1995), 60(17), 5721-5. (0.5 g) according to the method of D30.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Na].[C:25]([CH2:29][C:30]([O:32][CH3:33])=[O:31])(=[O:28])[CH2:26][CH3:27]>C1C=CC=CC=1>[C:25]([CH:29]([C:14](=[O:15])[CH:13]([O:12][C:11]1[CH:18]=[CH:19][C:8]([O:7][C:6]2[CH:20]=[CH:21][C:3]([C:2]([F:23])([F:22])[F:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)[CH3:17])[C:30]([O:32][CH3:33])=[O:31])(=[O:28])[CH2:26][CH3:27]
Reactant: CCC(=O)CC(=O)OC
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Agent: [Na]
Solvent: c1ccccc1
Product: CCC(=O)C(C(=O)OC)C(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
Following the procedure of Example 1, 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid chloride is added to the sodium salt of methyl propionylacetate in benzene to give methyl 2-propionyl-4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-oxopentanoate (cpd. 16 in Table A). This pentanoate is then heated with DMSO and NaCl to give 2-[4-(4-trifluoromethylphenoxy)phenoxy]-3,5-heptanedione (cpd. 16, Table B).