Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]([C:44]1[C:45]([OH:53])=[CH:46][C:47]3[O:51][CH2:50][CH2:49][C:48]=3[CH:52]=1)[C:31](=[O:43])[N:32]2[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[C:30]([C:44]1[C:45]([OH:53])=[CH:46][C:47]3[O:51][CH2:50][CH2:49][C:48]=3[CH:52]=1)([CH2:5][OH:16])[C:31](=[O:43])[N:32]2[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)OCC3)c2c(Br)cccc21
Product: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)OCC3)c2c(Br)cccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with ethyl [4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (99%): MS (ES+) m/z 463.2 (M+1).
Reaction SMILES: C(N(CC)CC)C.N1(C2C=CN=CC=2)CCCC1.[CH2:19]([C:21]([CH3:27])([CH2:25][CH3:26])[C:22](Cl)=[O:23])[CH3:20].[Si:28]([O:35][C@H:36]1[CH2:45][C@H:44]([OH:46])[C@H:43]2[C:38]([CH:39]=[CH:40][C@H:41]([CH3:64])[C@@H:42]2[CH2:47][CH2:48][C@H:49]2[O:54][C:53](=[O:55])[CH2:52][C@H:51]([O:56][Si:57]([C:60]([CH3:63])([CH3:62])[CH3:61])([CH3:59])[CH3:58])[CH2:50]2)=[CH:37]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C1C=CC=CC=1.C(OCC)(=O)C>[Si:28]([O:35][C@H:36]1[CH2:45][C@H:44]([O:46][C:22](=[O:23])[C:21]([CH2:25][CH3:26])([CH3:27])[CH2:19][CH3:20])[C@H:43]2[C:38]([CH:39]=[CH:40][C@H:41]([CH3:64])[C@@H:42]2[CH2:47][CH2:48][C@H:49]2[O:54][C:53](=[O:55])[CH2:52][C@H:51]([O:56][Si:57]([C:60]([CH3:63])([CH3:62])[CH3:61])([CH3:58])[CH3:59])[CH2:50]2)=[CH:37]1)([C:31]([CH3:32])([CH3:33])[CH3:34])([CH3:30])[CH3:29]
Reactant: CCC(C)(CC)C(=O)Cl
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Agent: c1cc(N2CCCC2)ccn1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCC(C)(CC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 99.6 %

Procedure:
0.76 ml (5.4 mmol) of triethylamine, 807 mg (5.4 mmol) of 4-(1-pyrrolidinyl)pyridine and 674 mg (4.5 mmol) of 2-ethyl-2-methylbutyryl chloride were added to a solution of 500 mg (0.91 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]-ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] in 10 ml of benzene and the resulting mixture was heated under reflux for 5 hours. At the end of this time, the reaction mixture was diluted with 50 ml of ethyl acetate. The diluted mixture was then washed with 30 ml of water, 30 ml of a 10% w/v aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, in that order. The organic phase was then dried over anhydrous magnesium sulfate, after which this phase was filtered. The filtrate was concentrated by evaporation under reduced pressure and the concentrate was purified by flash column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the-eluent, to give 601 mg (100% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1.[Br:18][CH2:19][C:20](=O)[CH3:21]>C(O)C>[BrH:18].[CH3:21][C:20]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=3)=[N:4][N:3]2[CH:19]=1
Reactant: Nc1ccc(-c2cccc(C(F)(F)F)c2)nn1
Reactant: CC(=O)CBr
Solvent: CCO
Product: Br
Product: Cc1cn2nc(-c3cccc(C(F)(F)F)c3)ccc2n1

Procedure:
A 1.5 g sample of 3-amino-6-[3-(trifluoromethyl)phenyl]pyridazine, 1.23 g of bromoacetone and 50 ml of ethanol was refluxed for 18 hours. The volatiles were removed in vacuo and the residue dissolved in dichloromethane. The solution was treated with activated carbon, filtered, and concentrated. The residue was crystallized from dichloromethane-hexane to give 1.0 g of the desired product as cream colored crystals, mp 219°-221° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=3)[C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:28]([C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=1)[CH3:29]>>[I:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:28]([C:30]4[CH:35]=[N:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[CH3:29])=[C:14]([O:19][CH3:20])[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(Cn2cnc3cc(I)cnc32)ccc1O
Reactant: COc1ccc(C(C)Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C(C)Oc2ccc(Cn3cnc4cc(I)cnc43)cc2OC)cn1
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 49.3 %

Procedure:
To a stirred mixture of 4-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-methoxyphenol (1.32 g, 3.46 mmol) and potassium carbonate (1.30 g, 9.41 mmol) in cetonitrile (25 mL) was added 5-(1-chloroethyl)-2-methoxypyridine (0.72 g, 4.20 mmol). The mixture was heated at 100° C. After 6.5 h, an additional quantity 5-(1-chloroethyl)-2-methoxypyridine (0.300 g, 1.75 mmol) was added, and heating was continued. After 22 h, the mixture was allowed to cool to room temperature and was partitioned between water and 1:5 ethyl acetate/diethyl ether. The phases were separated, and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with water, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (40 g SiO2 column, 0-10% 0.01 M ammonia in methanol/dichlormethane elute) afforded 0.88 g (49%) of 6-iodo-3-(3-methoxy-4-(1-(6-methoxypyridin-3-yl)ethoxy)benzyl)-3H-imidazo[4,5-b]pyridine as an impure solid.
Reaction SMILES: C(#[N:3])C.[Cl:4][C:5]1[C:6]([F:14])=[N:7][C:8]([F:13])=[C:9]([F:12])[C:10]=1F.N>O>[NH2:3][C:10]1[C:9]([F:12])=[C:8]([F:13])[N:7]=[C:6]([F:14])[C:5]=1[Cl:4]
Reactant: CC#N
Reactant: Fc1nc(F)c(Cl)c(F)c1F
Agent: N
Solvent: O
Product: Nc1c(F)c(F)nc(F)c1Cl
Reaction time: 0.5 h

Procedure:
To 100 ml of acetonitrile was dissolved 20.5 g of 3-chloro-2,4,5,6-tetrafluoropyridine, and 30 ml of 25% aqueous solution of ammonia was added in three portions while the mixture was stirred and cooled with water, and the stirring was continued for another 30 minutes. The solution was concentrated under reduced pressure. After adding 200 ml of chloroform to the solid residue, the solution was washed with 50 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the precipitate was collected by filtration to obtain 16.6 g of the title compound as colorless flake crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH:10]=[CH2:11])[C:4]=1[CH3:12])#[N:2].[CH3:13][SiH:14]([CH3:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1CCCCC1.C(O)(C)C.O.Cl.Cl.Cl[Pt](Cl)(Cl)Cl>[CH3:13][Si:14]([CH3:21])([CH2:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[C:4]=1[CH3:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[SiH](C)c1ccccc1
Reactant: C=CCc1cccc(C#N)c1C
Agent: Cl[Pt](Cl)(Cl)Cl
Agent: Cl
Solvent: O
Solvent: C1CCCCC1
Solvent: CC(C)O
Product: Cc1c(C#N)cccc1CCC[Si](C)(C)c1ccccc1
Temperature: 55 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
9.0 g of 1-cyano-2-methyl-3-prop-2-enylbenzene are dissolved in 100 ml of absolute cyclohexane, and 7.75 g of dimethylphenylsilane are added at room temperature. 0.1 g of hexachloroplatinic acid hexahydrate, dissolved in 2 ml of absolute isopropanol, is added to this mixture. The reaction mixture is stirred for 3 hours at 55° C. The solvent is removed by distillation in a rotary evaporator. High boiling components are separated off by distillation under reduced pressure (condensate 82°-105° C./0.1 mbar). The residue is purified by column chromatography (silica gel/toluene). 12.2 g of dimethyl-3-(2'-methyl-3'-cyanophenyl)-propylphenylsilane are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:20][CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](F)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:22]1([C@@H:28]([NH2:30])[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:20][CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:30][C@H:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:29])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CCc1nc(-c2cccc(Cl)c2)c(-c2ccnc(F)c2)s1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCc1nc(-c2cccc(Cl)c2)c(-c2ccnc(N[C@@H](C)c3ccccc3)c2)s1
Product: Cl
Temperature: 150 °C
Reaction time: 16 h
Yield: 107.6 %

Procedure:
A mixture of 4-(3-chlorophenyl)-2-ethyl-5-(2-fluoro-4-pyridyl)-1,3-thiazole (0.35 g, 1.1 mmol) and (S)-1-phenylethylamine (1.4 mL, 11 mmol) was stirred at 150° C. for 16 hrs. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The obtained oil was treated with 10% hydrogen chloride-methanol to give the title compound (0.27 g, yield 56%).
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[NH:6][C:5](=[S:9])[N:4]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]=1[NH:15][C:16]([CH:18]1[CH2:21][CH2:20][CH2:19]1)=O.[OH-].[Na+]>O.CO>[CH:18]1([C:16]2[NH:1][C:2]3[C:7](=[O:8])[NH:6][C:5](=[S:9])[N:4]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]=3[N:15]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: CCCCCn1c(NC(=O)C2CCC2)c(N)c(=O)[nH]c1=S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCn1c(=S)[nH]c(=O)c2[nH]c(C3CCC3)nc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
The mixture of N-(5-amino-6-oxo-3-pentyl-2-thioxo-1,2,3,6-tetrahydropyrimidin-4-yl)cyclobutanecarboxamide (720 mg, 2.3 mmol) and 2.5 M of sodium hydroxide in water (25 mL) and methanol (25 mL) was stirred at 70° C. for 1 hour. After cooling to room temperature, the reaction mixture was concentrated to remove methanol and then acidified to pH=5. The precipitate formed was filtered and dried to yield the desired product (500 mg, 73.7%). LCMS calculated for C14H21N4OS(M+H): 293.1; found: 293.1.
Reaction SMILES: C[N:2]1CCOCC1.[C:8]1([CH2:14][S:15](Cl)(=[O:17])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)Cl>C(#N)C>[CH2:14]([S:15]([NH2:2])(=[O:17])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CN1CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: NS(=O)(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 118.1 %

Procedure:
To a solution of 5 (7.54 g, 0.0298 mole; see Example 5) and 4-methylmorpholine (9.04 g, 0.0894 mole, 9.83 mL) in 300 mL of anhydrous acetonitrile at 0° C. under N2 was added α-toluene-sulfonyl chloride (11.36 g, 0.0596 mole) in one portion. The solution was stirred at 0° C. for 1 hour and allowed to warm. to and stir at ambient temperature for 19 hours. The solution was filtered and evaporated. The crude residue was purified by flash chromatography on silica gel using a hexane, CH2Cl2: 4,1 to CH2Cl2 gradient system and afforded 12.05 g (99% yield) of product 6 as waxy reddish solid, mp 62-63° C. TLC (silica; CH2Cl2), Rf=0.45.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:19][C:20]1([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:22][CH2:21][C:20]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:19])[CH2:25][CH2:24]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CC1(NC(=O)OC(C)(C)C)CCNCC1
Solvent: CO
Product: CC1(NC(=O)OC(C)(C)C)CCN(c2nc(Cl)nc3c2CCC3c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 168 h
Yield: 24.4 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (400 mg, 1.413 mmol) in MeOH (14.100 mL) was added tert-butyl 4-methylpiperidin-4-ylcarbamate (303 mg, 1.413 mmol). The resulting mixture was stirred at RT for 7 days. At that time, the reaction mixture was concentrated in vacuo. Purification by flash chromatography (Silica, EtOAc/Hexanes) gave tert-butyl 1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-methylpiperidin-4-ylcarbamate (159 mg, 0.345 mmol, 24.41% yield) as a yellow foam. LC-MS (M+H)+=461.2. 1H NMR (500 MHz, MeOD) δ ppm 7.12-7.22 (2 H, m), 6.98-7.09 (2 H, m), 4.19 (3 H, d, J=2.14 Hz), 3.38-3.56 (2 H, m), 3.13-3.25 (1 H, m), 3.02-3.13 (1 H, m), 2.53-2.67 (1 H, m), 2.11-2.24 (2 H, m), 1.96-2.08 (1 H, m), 1.53-1.65 (2 H, m), 1.47 (9 H, s), 1.37 (3 H, s).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13](COCC[Si](C)(C)C)[CH:12]=2)=[O:10])[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2CC[C@H](O)CC2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)N[C@H]4CC[C@H](O)CC4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In a 25 mL round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (trans-4-hydroxycyclohexyl)amide (60 mg, 0.108 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (0.2 mL, 2.6 mmol) was added and the orange reaction mixture was stirred at room temperature for 15 h. Additional trifluoroacetic acid (0.7 mL) was added and the reaction stirred for an additional 5 h. The reaction mixture was then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (3 mL) and ethylenediamine (0.20 mL, 2.96 mmol) was added. The light yellow reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was sequentially washed with water, dichloromethane, ethyl acetate, and hexanes to afford 28 mg (60%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (trans-4-hydroxy-cyclohexyl)amide as a light yellow solid. MS: [M+H]+=525; 1H NMR (300 MHz, DMSO-d6) δ: 9.08 (s, 2H), 8.40 (s, 1H), 8.43 (d, J=1.0 Hz, 1H), 8.02 (d, J=1.0 Hz, 1H), 8.01 (s, 1H), 7.28 (dd, J=8.6, 2.0 Hz, 1H), 4.45-4.76 (m, 1H), 4.17 (s, 3H), 3.70-3.96 (m, 1H), 3.43-3.59 (m, 1H), 2.07 (d, J=11.1 Hz, 2H), 1.92 (d, J=10.6 Hz, 2H), 1.18-1.55 (m, 4H).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH2:12][CH2:13][CH2:14][OH:15]>CS(C)=O.C(OCC)(=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][CH2:13][CH2:14][OH:15])=[CH:6][CH:5]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: OCCCOc1ccc(Br)cc1
Reaction time: 2.5 h

Procedure:
Powdered sodium hydroxide (2.2 g) was added to a solution of 4-bromophenol (3.46 g) and 3-bromopropanol (2.36 ml) in DMSO (18 ml). The mixture was stirred vigorously at 20° for 2.5 h then diluted with ethyl acetate (100 ml) and washed successively with 2N hydrochloric acid (100 ml), water (100 ml×2) and brine. Concentration of the dried organic phase yielded the title compound (5.02 g) as a pale orange oil. T.l.c. (diethyl ether) Rf 0.32.
Reaction SMILES: N1CCCCC1.O=[CH:8][C:9]1[CH:17]=[CH:16][C:14]([OH:15])=[C:11]([O:12][CH3:13])[CH:10]=1.[CH3:18][O:19][C:20](=[O:24])[CH2:21][C:22]#[N:23]>C(O)C>[CH3:18][O:19][C:20](=[O:24])/[C:21](/[C:22]#[N:23])=[CH:8]/[C:9]1[CH:17]=[CH:16][C:14]([OH:15])=[C:11]([O:12][CH3:13])[CH:10]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: COC(=O)CC#N
Solvent: C1CCNCC1
Solvent: CCO
Product: COC(=O)/C(C#N)=C/c1ccc(O)c(OC)c1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
0.2 ml of piperidine were added carefully to a solution of 4.6 g (30 mmol) of vanillin, 3.4 ml (30.3 mmol) of cyanoacetic acid methyl ester and 0.5 ml of ethanol held at 45° C. The product started to precipitate on cooling to room temperature. The cold reaction mixture was diluted with 8 ml of ethanol, filtered and washed with cold ethanol to give 6.5 g (93%) of 2-cyano-(E)-3-(4-hydroxy-3-methoxyphenyl)acrylic acid methyl ester in form of yellow crystals.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH:9]([CH3:13])[CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:15].[Na+].[Cl-].[Na+]>CO.O>[C:1]1([S:7]([CH2:8][CH:9]([CH3:13])[CH2:10][CH2:11][OH:12])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(CCO)CSc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(CCO)CS(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.96 g of 4-phenylthio-3-methyl-1-butanol were dissolved in 100 ml of methanol, a solution of 2.57 g of sodium metaperiodate in 50 ml of water added, and the mixture stirred at room temperature overnight. Then, an aqueous solution of sodium chloride was added, the resulting mixture extracted with diethyl ether, the ether layer washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the ether distilled off. There was obtained a slightly yellow liquid. This was purified by silica gel column chromatography (developing solvent: methylene chloride-ethyl acetate) to give 1.60 g of a colorless to slightly yellow liquid. The characteristic signals of this substance on its 1H-NMR spectrum were as follows:
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.C(OCC)(=O)C>CO.Cl.O>[N:12]1([C:9]2[CH:8]=[CH:7][C:6]([CH:2]=[O:1])=[CH:11][CH:10]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: c1cc(N2CCOCC2)ccc1C1OCCO1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=Cc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(4-[1,3]dioxolan-2-yl-phenyl)-morpholine (690 mg, 2.933 mmol) in methanol (5 mL) was treated with 10 drops concentrated aqueous hydrochloric acid. The mixture was stirred at room temperature for 1 hour. To this solution was added 5 drops of water and stirring was continued for 2 hours at ambient temperature. The solution was then poured into ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (2×50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give 4-morpholin-4-yl-benzaldehyde as a tan waxy solid (550 mg, 98%).
Reaction SMILES: [Si:1]([O:8][C:9]([C:11]([F:27])([F:26])[C@H:12]([C@@H:14]([CH:16]([C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:17])[OH:15])[OH:13])=[O:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[F:34][C:35]([F:48])([F:47])[S:36]([O:39]S(C(F)(F)F)(=O)=O)(=[O:38])=[O:37]>ClCCl>[Si:1]([O:8][C:9]([C:11]([F:26])([F:27])[C@:12]([O:39][S:36]([C:35]([F:48])([F:47])[F:34])(=[O:38])=[O:37])([C@@H:14]([CH:16]([C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:17])[OH:15])[OH:13])=[O:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OC(=O)C(F)(F)[C@@H](O)[C@H](O)C(O)C(=O)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC(=O)C(F)(F)[C@](O)(OS(=O)(=O)C(F)(F)F)[C@H](O)C(O)C(=O)c1ccccc1
Temperature: -20 °C
Reaction time: 0.67 h
Yield: 85.9 %

Procedure:
To a solution of 2.3 gm (5.9 mMol) 1-t-butyldimethylsilyloxy-5-benzoyl-2-deoxy-2,2-difluoroxylose in dichloromethane (100 mL) were added 7.2 mL (88.5 mMol) pyridine and the reaction mixture was cooled to -20° C. To this was then added a solution of 1.5 mL (8.9 mMol) trifluoromethanesulfonic anhydride in dichloromethane (20 mL) dropwise at such a rate as to maintain the temperature between -5° and -20° C. The reaction mixture was stirred for 40 minutes at -15° C. The reaction mixture was then allowed to warm to room temperature and was washed with saturated aqueous sodium bicarbonate. The remaining organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 2.8 gm (90%) of the desired compound as a yellow oil. FD-MS: m/e=463(M-57, loss of t-butyl).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH:20]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)([CH3:22])[CH3:21]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:27][C:26]4[CH:28]=[CH:29][C:23]([CH:20]([CH3:22])[CH3:21])=[CH:24][CH:25]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: CC(C)c1ccc(N)cc1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: CC(C)c1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with 4-isopropylaniline gave N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-isopropylphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.30 (s, 1H), 10.50 (s, 1H), 8.22 (d, 1H, J=5.4 Hz). 7.37 (d, 1H, J=8.4 Hz), 7.26 (d, 1H, J=3 Hz), 7.18 (s, 1H), 7.15 (s, 1H), 7.06 (dd, 1H, J=3.3 and 8.7 Hz), 6.81 (d, 1H, J=8.7 Hz), 4.23 (s, 4H), 2.85 (sept., 1H, J=7.2 Hz), 1.17 (d, 6H, J=6.9 Hz); LCMS: ret. time: 24.91 min.; purity: 95%; MS (m/e): 381 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH2:27]([N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][C:31]1=[O:40])[C:28]#[CH:29]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:29]#[C:28][CH2:27][N:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33][CH2:32][C:31]3=[O:40])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: C#CCN1C(=O)CCc2ccccc21
Reactant: Fc1ccccc1C1=NCc2nnc(C(F)(F)F)n2-c2ccc(I)cc21
Product: O=C1CCc2ccccc2N1CC#Cc1ccc2c(c1)C(c1ccccc1F)=NCc1nnc(C(F)(F)F)n1-2

Procedure:
The title compound was prepared by coupling 6-(2-fluorophenyl)-1-(trifluoromethyl)-8-iodo-4H-[1,2,4]triazolo [4,3-a][1,4]benzodiazepine with 3,4-dihydro-1-(2-propynyl)-2(1H)-quinolinone under the conditions used in Example 37. The product was purified by chromatoqraphy over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride. The clean fractions were combined and evaporated and the residue was crystallized from ethyl acetate to yield colorless crystals of 1-{3-[6-(2-fluorophenyl)-1-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepin-8-yl]-2-propynyl}-3,4-dihydro-2(1H)-quinolinone with m.p. 193°-196°.