Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([Cl:10])=[CH:6][C:7]=1[NH:8][CH3:9].[CH2:13](Cl)Cl>C(O)(=O)C.C(OCC)(OCC)OCC.C(OCC)(=O)C>[Cl:10][C:5]1[N:4]=[C:3]([C:11]#[N:12])[C:2]2[N:1]=[CH:9][N:8]([CH3:13])[C:7]=2[CH:6]=1
Reactant: CNc1cc(Cl)nc(C#N)c1N
Reactant: ClCCl
Solvent: CCOC(C)=O
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: Cn1cnc2c(C#N)nc(Cl)cc21
Temperature: 150 °C

Procedure:
The suspension of 3-amino-6-chloro-4-methylamino-pyridine-2-carbonitrile (1.8 g) in DCM (5 ml), acetic acid (1.5 ml) and triethyl orthoformate (10 ml) was heated in microwave at 150° C. for 30 minutes. The mixture was then diluted with ethyl acetate (200 ml), washed with 10% sodium carbonate (100 ml), dried over sodium sulphate, solvent removed under reduced pressure, DCM (5 ml) was then added to the residue, some product crashed out and collected by filtration (0.5 g), the rest was then columned on silica gel using ethyl acetate-heptane (55:45) as eluant to give another 0.8 g of expected product (a total of 1.3 g product). 1H NMR (CDCl3) δ: 8.1 (s, 1H), 7.6 (s, 1H), 3.93 (s, 3H). MS m/z 193 (M+H).
Reaction SMILES: C(C(C(=O)O)[C@@H](C(N[C@@H](C(O)=O)C)=O)NC([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)C1C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](OCC)=[O:41].[O:45]1CCCC1>>[O:13]=[CH:14][C:15]1[CH:16]=[CH:17][C:18]([OH:45])=[C:19]([O:41][CH3:40])[CH:20]=1
Reactant: C[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O)C(=O)O
Reactant: CCOC(=O)Cl
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(C=O)ccc1O
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
To a 250 ml. three-necked flask fitted with a stopper, thermometer, drying tube and magnetic stirring bar was added 4.28 g. (0.010 mole) of beta-benzyl-N-benzyloxycarbonyl-L-aspartyl-D-alanine, 75 ml. tetrahydrofuran and 1.53 ml. (0.011 mole) triethylamine. The mixture was cooled to -10° C., 1.05 ml. (0.011 mole) ethyl chloroformate was added, stirred for 20 minutes, cooled to -35° C. and 1.11 g. (0.010 mole) of dicyclopropylcarbinylamine added. The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The mixture was poured into 150 ml. water, extracted with 250 ml. of ethyl acetate and the organic phase washed with 5% aqueous sodium bicarbonate (2×75 ml.), 3 M hydrochloric acid (2×75 ml.), brine (1×100 ml.) and dried over anhydrous magnesium sulfate. The dried extract was evaporated to dryness in vacuo to provide a colorless solid which was recrystallized from 75 ml. of boiling ethyl acetate to obtain 3.78 g. (72%) of diblocked amide, M.P. 164°-165° C. Thin-layer chromatography (TLC) on silica gel, eluting with 1:1 ethyl acetate/hexane gave a single spot, Rf 0.40 with vanillin spray reagent. An additional 0.65 g. was recovered from the mother liquors.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4](I)[CH:3]=1.[Li]C(CC)C.CCCCCC.C(=O)=O.[CH3:24][C:25]([CH3:27])=[O:26].B(F)(F)F>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH2:24][C@H:25]([OH:26])[CH3:27])[CH:3]=1
Reactant: Cc1ccc(F)cc1I
Reactant: CC(C)=O
Agent: FB(F)F
Agent: O=C=O
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C[C@@H](C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An oven dried 3-necked round bottom flask (rbf), which contained a magnetic stirring bar, was sealed with rubber septum having a thermometer. While cooling to rt, the flask was evacuated and backfilled with argon. This sequence was repeated 3 times. In the flask, a solution of 4-fluoro-2-iodo-1-methylbenzene (25 g, 105.9 mmol) in anhydrous THF (800 mL) was stirred at −78° C. in a dry ice/acetone bath under argon gas. After 30 min, 1.4 M sec-BuLi in hexane (83.2 mL, 116.5 mmol) was added dropwise at that temperature for 20 min. After adding, the mixture was stirred at −78° C. in the dry ice/acetone bath for 30 min, and stirred more for 30 min without the bath. And then, the solution was cooled again in the dry ice/acetone to −78° C. and a solution of R-(+)-propylene (8 g, 137.7 mmol) in 50 mL anhydrous THF was added dropwise at the temperature for 10 min. And then, the mixture was cooled to −105° C. and 46.5% solution of BF3 in diethyletherate (19.6 mL) was added dropwise. And the mixture was stirred at −78° C. for 2 h, and then quenched slowly by sat. NH4Cl at −78° C. and stirred at ambient temperature for overnight. Water (20 mL) was added and extracted with EtOAc, dried over anhydrous MgSO4, evaporated and purified by column chromatography (DCM/hexane 9/1) to give (R)-1-(5-fluoro-2-methylphenyl)propan-2-ol (F-1) as pale yellowish oil.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C@H:19]([NH2:23])[C:20]([OH:22])=O)[CH2:14][CH2:13]1.Cl.Cl.[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH2:34][CH2:35][NH2:36])=[CH:29][CH:28]=1>>[Cl:11][C:10]1[C:4]2[O:3][C:2]([NH:23][C@@H:19]([CH2:18][CH:15]3[CH2:14][CH2:13][CH2:12][CH2:17][CH2:16]3)[C:20]([NH:36][CH2:35][CH2:34][NH:33][C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)=[O:22])=[N:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Clc1nc2cccc(Cl)c2o1
Reactant: NCCNc1ccc(F)cc1
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Agent: Cl
Product: O=C(NCCNc1ccc(F)cc1)[C@H](CC1CCCCC1)Nc1nc2cccc(Cl)c2o1

Procedure:
The title compound was prepared from 2,7-dichlorobenzooxazole, L-cyclohexylalanine and N1-(4-Fluoro-phenyl)-ethane-1,2-diamine-2HCl using the procedure analogous to that described in example 2. 1H NMR (DMSO-d6, 400 MHz) δ 8.45 (d, 1H, J=8.0 Hz), 8.17 (t, 1H, J=5.6 Hz), 7.13 (dd, 1H, J=1.2 Hz, J=7.6 Hz), 7.06 (dd, 1H, J=7.6 Hz), 7.00 (dd, 1H, J=7.6 Hz, J=1.2 Hz), 6.84(m, 2H), 6.51(m, 2H), 4.19(m, 1H), 3.15(m, 2H), 2.98(m, 2H), 1.55(m, 7H), 1.30(m, 1H), 1.05(m, 3H), 0.83(m, 2H). HPLC-MS calcd. for C24H28ClFN4O2(M+H+) 459.19. found 459.5.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[K+].[Cl:8][C:9]1[CH:24]=[CH:23][C:12]2[C:13]3[CH:19]=[CH:18]C(C([O-])=O)=[CH:16][C:14]=3[S:15][C:11]=2[CH:10]=1>C1C=CC=CC=1>[Cl:4][C:2]([C:1]1[CH:18]=[CH:19][C:13]2[C:12]3[CH:23]=[CH:24][C:9]([Cl:8])=[CH:10][C:11]=3[S:15][C:14]=2[CH:16]=1)=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C([O-])c1ccc2c(c1)sc1cc(Cl)ccc12
Agent: [K+]
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc2c(c1)sc1cc(Cl)ccc12

Procedure:
A solution of 10.5 g. of oxalyl chloride in 100 ml. of benzene was added, with stirring, to a suspension of 16.53 g. of 7-chlorodibenzothiophene-3-carboxylic acid potassium salt in 100 ml. of benzene. The mixture was stirred and refluxed for two hours and then filtered. On distillation to dryness on the steam bath in vacuo 9 g. of crude 3-chlorocarbonyl-7-chlorodibenzothiophene was obtained as a residue.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[CH2:23]>O1CCOCC1>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:23][CH2:22][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: C=Cc1ccccn1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Solvent: C1COCCO1
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCc2ccccn2)C1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (1.0 g--see Preparation 8), 2-vinylpyridine (0.5 g) and 1,4-dioxane (10 ml) was heated under reflux for 20 hours. On cooling to room temperature the mixture was filtered and the filtrate was diluted with water (100 ml) then extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a brown oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (2% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.31 g.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1.[Al+3].[Cl-].[Cl-].[Cl-].[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:28][C:29](Cl)=[O:30]>C(Cl)Cl>[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:28][C:29]([C:14]1[C:8]2[C:9](=[N:10][CH:11]=[C:6]([C:5]#[C:4][CH2:3][N:2]([CH3:1])[CH3:15])[CH:7]=2)[NH:12][CH:13]=1)=[O:30]
Reactant: CN(C)CC#Cc1cnc2[nH]ccc2c1
Reactant: O=C(Cl)Cc1cccc(F)c1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CN(C)CC#Cc1cnc2[nH]cc(C(=O)Cc3cccc(F)c3F)c2c1
Reaction time: 8 h

Procedure:
189 mg of crude Dimethyl-[3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-prop-2-ynyl]-amine was stirred in 5 ml of DCM with AlCl3 (4 equivalents) for 30 minutes. Two equivalents of (2,3-Difluoro-phenyl)-acetyl chloride were added and the reaction was stirred in a sealed tube overnight. The LC/MS showed the reaction to be complete and was worked-up under standard conditions. Normal phase column chromatography yielded 101 mg of 2-(2,3-Difluoro-phenyl)-1-[5-(3-dimethylamino-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-ethanone with a yield over two steps of 33%. LC/MS retention time of 1.83 minutes. M+ 354.17, M− 352.1
Reaction SMILES: [C:1]1([C@H:11]([NH:13][CH:14]2[CH2:17][N:16](C(OCC3C=CC=CC=3)=O)[CH2:15]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>CO.[C].[Pd]>[C:1]1([C@H:11]([NH:13][CH:14]2[CH2:17][NH:16][CH2:15]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](NC1CN(C(=O)OCc2ccccc2)C1)c1cccc2ccccc12
Agent: [Pd]
Solvent: CO
Product: C[C@@H](NC1CNC1)c1cccc2ccccc12
Reaction time: 4 h
Yield: 77.5 %

Procedure:
To a solution of 5.0 g of 1-benzohydrylazetidin-3-one dissolved in 75 ml of toluene was added 2.98 ml of benzyloxycarbonyl chloride, and the mixture was stirred at 80° C. for 4 hours. The reaction mixture was evaporated, and then, to the residue were added water and ethyl acetate, the mixture was stirred and the liquids were separated. The organic layer was washed with water and a saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1), and then, hexane was added thereto, and after collecting the precipitate by filtration, it was washed with hexane to obtain 2.73 g of benzyl 3-oxoazetidine-1-carboxylate. (3) To a solution of 8.51 g of benzyl 3-oxoazetidine-1-carboxylate and 7.10 g (R)-(+)-1-(1-naphthyl)ethylamine dissolved in 170 ml of methylene chloride, 7.49 g of magnesium sulfate was added to the solution. The mixture was stirred at room temperature for 3 hours, and then, 9.5 ml of acetic acid and 13.18 g of sodium triacetoxy borohydride were added thereto, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution to make the mixture basic, chloroform was added to the same and the mixture was stirred, and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to obtain 7.90 g of benzyl 3-[(R)-1-(naphthalen-1-yl)ethylamino]azetidine-1-carboxylate. (4) To a solution of 9.45 g of benzyl 3-[(R)-1-(naphthalen-1-yl)ethylamino]azetidine-1-carboxylate dissolved in 190 ml of methanol, 1 g of palladium carbon (10% wet) was added thereto, and the reaction was carried out under hydrogen atmosphere at room temperature for 4 hours. Palladium carbon was removed, the solvent was evaporated, and the residue was purified by NH silica gel column chromatography (chloroform:methano1=1:0→19:1) to obtain 4.60 g of 3-[(R)-1-(naphthalen-1-yl)ethylamino]azetidine. To a solution of 4.60 g of 3-[(R)-1-(naphthalen-1-yl)ethylamino]azetidine dissolved in 30 ml of ethyl acetate, under ice-cooling, 13 ml of a solution of 4M hydrochloric acid in ethyl acetate was added dropwise, and the mixture was stirred for a while.
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:14][C:15]([CH3:33])([C:17]2[N:21]([CH3:22])[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])=[N:19][N:18]=2)[CH3:16])=[C:10]([CH2:12][NH2:13])[CH:11]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[ClH:4].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:14][C:15]([CH3:33])([C:17]2[N:21]([CH3:22])[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:31])([F:30])[F:32])=[N:19][N:18]=2)[CH3:16])=[C:10]([CH:11]=1)[CH2:12][NH:13][C:1](=[O:3])[CH3:2]
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1CN
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1cc(Cl)ccc1OC(C)(C)c1nnc(-c2ccccc2C(F)(F)F)n1C
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of acetyl chloride (67 μl) in dichloromethane (1 ml) was slowly added to a solution of 1-[5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]methanamine (200 mg) and triethylamine (0.2 ml) in dichloromethane (4 ml), followed by stirring at room temperature for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution to cease the reaction, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=97:3) and dissolved in ethyl acetate, and 4M hydrogen chloride-ethyl acetate was added thereto, followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure and the residue was washed with diisopropylether to obtain N-[5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzyl]acetamide monohydrochloride (166 mg) as an amorphous.
Reaction SMILES: NC1N=[C:6](N2CCC3(CN[C@H](C(OC(C)C)=O)C3)CC2)[CH:5]=[C:4](O[C@H](C2C=CC(C3C=CC(C)=C(C)C=3)=CC=2N2C=CC(C)=N2)C(F)(F)F)N=1.[NH2:50][C:51]1[N:56]=[C:55]([N:57]2[CH2:69][CH2:68][C:60]3([CH2:64][NH:63][C@H:62]([C:65]([OH:67])=[O:66])[CH2:61]3)[CH2:59][CH2:58]2)[CH:54]=[C:53]([O:70][C@H:71]([C:76]2[CH:81]=[CH:80][C:79]([Cl:82])=[CH:78][C:77]=2[C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)[C:72]([F:75])([F:74])[F:73])[N:52]=1>>[NH2:50][C:51]1[N:56]=[C:55]([N:57]2[CH2:58][CH2:59][C:60]3([CH2:64][NH:63][C@H:62]([C:65]([O:67][CH:5]([CH3:6])[CH3:4])=[O:66])[CH2:61]3)[CH2:68][CH2:69]2)[CH:54]=[C:53]([O:70][C@H:71]([C:76]2[CH:81]=[CH:80][C:79]([Cl:82])=[CH:78][C:77]=2[C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)[C:72]([F:75])([F:74])[F:73])[N:52]=1
Reactant: Nc1nc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1
Reactant: Cc1ccn(-c2cc(-c3ccc(C)c(C)c3)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)OC(C)C)C4)nc(N)n2)C(F)(F)F)n1
Product: CC(C)OC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-c4ccccc4)C(F)(F)F)nc(N)n3)CC2)CN1

Procedure:
The title compound was prepared as described for (S)-isopropyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (Example 67a) starting with (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 34c).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][C:21](=O)[CH2:22][C:23]1[CH:28]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:26]([O:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39])=[C:25]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:24]=1.CN(C)C=[O:48]>>[CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:23]2[CH:24]=[C:25]([C:40]([CH3:42])([CH3:41])[CH3:43])[C:26]([O:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39])=[C:27]([C:29]([CH3:30])([CH3:32])[CH3:31])[CH:28]=2)=[O:48])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Reactant: COCCOCOc1c(C(C)(C)C)cc(CC(=O)CCCBr)cc1C(C)(C)C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(=O)c1ccc(OCCCCC(=O)c2cc(C(C)(C)C)c(OCOCCOC)c(C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4-Hydroxy-alpha-oxobenzeneacetic acid ethyl ester (1.44 g) and 55% sodium hydride (0.36 g) in dimethylformamide (30 mL) was stirred for 20 minutes and then treated with 5-bromo-1-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy) methoxy]phenyl]pentanone (3.4 g) in dimethylformamide (6 mL). The mixture was stirred at room temperature for 20 hours and then after an additional 4 hours at 50° C., it was worked up as in Example 20. The residual oil was purified by HPLC (ethyl acetate-toluene; 1:17) to give 2.7 g of 4-[5-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy) methoxy]phenyl]-5-oxopentyloxy]-alpha-oxobenzeneacetic acid ethyl ester as an oil. A solution of the above 4-[5-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy) methoxy]phenyl]-5-oxopentyloxy]-alpha-oxobenzeneacetic acid ethyl ester (2.1 g) was dissolved in dichloromethane (20 mL) containing trifluoroacetic acid (1.1 mL) was stirred at room temperature for 31 hours, then saturated sodium bicarbonate solution was added (25 mL). The separated organic layer was dried (MgSO4) and evaporated and the crude product was purified by HPLC (ethyl acetate-hexane; 4:21). Trituration of the resulting material with hexane afforded 1.4 g of 4-[5-[3,5-bis(1,1-dimethylethyl) -4-hydroxyphenyl]-5-oxopentyloxy]-alpha-oxobenzeneacetic acid ethyl ester, mp 95°-96° C.
Reaction SMILES: C(O)(C)C.[O:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11].[NH2:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[C:21](Cl)[N:20]=1>O>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:19]([NH2:18])=[N:20][C:21]([N:15]3[CH2:14][CH2:13][N:12]([C:10]([CH:6]4[O:5][CH2:9][CH2:8][CH2:7]4)=[O:11])[CH2:17][CH2:16]3)=[N:22][C:23]2=[CH:24][C:25]=1[O:31][CH3:32]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(C1CCCO1)N1CCNCC1
Solvent: O
Solvent: CC(C)O
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Yield: 108.1 %

Procedure:
To a solution of iso-propanol (290 ml), water (50 ml) and N-(2-tetrahydrofuroyl)piperazine (20 g) were added, while stirring, 4-amino-2-chloro-6,7-dimethoxyquinazoline (22.2 g). The reaction mixture was heated to reflux and the reflux was maintained for about 35 hours. Then the reaction mixture was cooled to room temperature and stirred at this temperature for about 12 hours. The crystals were collected by filtration, washed with iso-propanol and dried in vacuo at 40° C. to yield 38.8 g (94%) of Terazosin.HCl dihydrate. See Trial K in Table I. Trial L was performed using a 5% percent volume of water.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].[OH-].[Na+]>CO>[CH3:15][O:14][C:10](=[O:13])[CH2:11][CH2:12][N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: C=CC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)CCn1cc(C)c(=O)[nH]c1=O

Procedure:
Thymine (14 g, 0.11 mol) was suspended in methanol. Methyl acrylate (39.6 mL, 0.44 mol) was added, along with catalytic amounts of sodium hydroxide. The solution was refluxed in the dark for 45 h, evaporated to dryness in vacuo, and the residue dissolved in methanol (8 mL) with heating. After cooling in an ice bath, the product was precipitated by addition of ether (20 mL), isolated by filtration, washed with ether (3×15 mL), and dried over sicapent, in vacuo. Yield: 11.23 g (48%). M.p. 112°-119° C. Anal. for C9H12N2O4, found calc.) C: 51.14 (50.94) H: 5.78 (5.70) N: 11.52 (13.20). The compound showed satisfactory 1H and 13C-NMR spectra.
Reaction SMILES: [I-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])C=CC=CC=1.CC(C)([O-])C.[K+].[NH2:33][C:34]1[N:39]=[C:38]([N:40]([CH3:47])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:37]=[C:36]([C:48]2[N:52]=[C:51]([N:53]3[CH2:58][CH2:57][C:56](=O)[CH2:55][CH2:54]3)[O:50][N:49]=2)[N:35]=1>O1CCOCC1.C(Cl)Cl>[CH3:47][N:40]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:38]1[N:39]=[C:34]([NH2:33])[N:35]=[C:36]([C:48]2[N:52]=[C:51]([N:53]3[CH2:54][CH2:55][C:56](=[CH:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH2:57][CH2:58]3)[O:50][N:49]=2)[N:37]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(N3CCC(=O)CC3)n2)n1
Reactant: FC(F)(F)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(N3CCC(=CCC(F)(F)F)CC3)n2)n1
Reaction time: 0.17 h
Yield: 11.9 %

Procedure:
To a solution of triphenyl-(3,3,3-trifluoro-propyl)-phosphonium iodide (146 mg, 0.30 mmol) in anhydrous dioxane (10 mL) at 0 C under nitrogen was added potassium tert-butoxide (34 mg, 0.3 mmol) portion-wise. The suspension was stirred for 10 min at 0 C and then added drop-wise to a solution of 1-{3-[4-amino-6-(methyl-phenyl-amino)-[1,3,5]triazin-2-yl]-[1,2,4]oxadiazol-5-yl}-piperidin-4-one (Intermediate 131, 55 mg, 0.150 mmol) in anhydrous dioxane (10 mL). The resulting reaction mixture was stirred at room temperature for 16 h and evaporated to dryness. The solid obtained was dissolved in DCM (25 mL) and washed with water (25 mL), a saturated ammonium chloride aq. solution (25 mL) and brine (25 mL). The organic phase was dried over magnesium sulfate, evaporated to dryness and purified by preparative HPLC-MS (Method B) to afford the title compound as an off-white solid (8 mg, 12%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:8]2[C:13]([N:14]=[C:15]3[C:20]=1[CH:19]=[C:18]([O:21][CH3:22])[CH:17]=[CH:16]3)=[CH:12][CH:11]=[C:10]([O:23][CH3:24])[CH:9]=2.[CH:28]([N:31]=[C:32]=[O:33])([CH3:30])[CH3:29].C(N(CC)CC)C>C(Cl)Cl>[CH:28]([NH:31][C:32]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:8]2[C:13]([N:14]=[C:15]3[C:20]=1[CH:19]=[C:18]([O:21][CH3:22])[CH:17]=[CH:16]3)=[CH:12][CH:11]=[C:10]([O:23][CH3:24])[CH:9]=2)=[O:33])([CH3:30])[CH3:29]
Reactant: COc1ccc2nc3ccc(OC)cc3c(Nc3cccc(CO)c3)c2c1
Reactant: CC(C)N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2nc3ccc(OC)cc3c(Nc3cccc(COC(=O)NC(C)C)c3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
A mixture of 9-(3'-hydroxymethylanilino)-2,7-dimethoxyacridine, (300 mg, 0.66 mmol), isopropyl isocyanate (1 ml) and triethylamine (2 ml) in methylene chloride (20 ml) is stirred at room temperature for 90 minutes, and then concentrated in vacuo. The residue is chromatographed on a silica gel column using commerical chloroform as the eluent to give the 9-[3'-(isopropylaminocarbonyloxymethyl)-anilino]-2,7-dimethoxyacridine, (246 mg, 84%) as a yellow solid, mp 148°-149° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH2:18]=[CH:19][CH2:20][N:21]=[C:22]=[O:23]>>[CH2:18]=[CH:19][CH2:20][NH:21][C:22]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: C=CCN=C=O
Product: C=CCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 73.1 %

Procedure:
Beginning with 0.15 gm (0.65 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.070 mL (0.78 mMol) prop-1-en-3yl isocyanate, 0.149 gm (73%) of the title compound were recovered essentially by the procedure of Example 122. An analytical sample was crystallized from aqueous ethanol. m.p.=203° C. (dec.) MS(m/e): 313(M+) Calculated for C17H23N5O: Theory: C, 65.15; H, 7.40; N, 22.35. Found: C, 65.15; H, 7.65; N, 22.22.