Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]([OH:17])[C:15]#[CH:16])[CH:5]=[C:4]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:3]1=2.Cl>CCCCCCC.C(OC=C)(=O)C.C([O-])([O-])=O.[K+].[K+].CO>[CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C@H:14]([OH:17])[C:15]#[CH:16])[CH:5]=[C:4]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:3]1=2
Reactant: C#CC(O)c1cc(OCCOCC)c2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: C=COC(C)=O
Solvent: CO
Product: C#C[C@@H](O)c1cc(OCCOCC)c2c(c1)C(C)(C)CCC2(C)C
Temperature: 38 °C
Reaction time: 72 h
Yield: 41 %

Procedure:
36 g (110 mmol) of 1-[5,5,8,8-tetramethyl-4-(2-ethoxyethoxy)-5,6,7,8-tetrahydronaphth-2-yl]prop-2-yn-1-ol (Example 2b) are dissolved in 75 mL of heptane and 10.2 ml of vinyl acetate. 7.26 g of enzyme PS30 are added, and the reaction medium is stirred and heated to 38° C. After 72 hours, the reaction medium is filtered and concentrated under reduced pressure. Two products are separated out by chromatography: 1-[5,5,8,8-tetramethyl-4-(2-ethoxyethoxy)-5,6,7,8-tetrahydronaphth-2-yl]prop-2-yn-1-ol (R)-acetate and (S)-1-[5,5,8,8-tetramethyl-4-(2-ethoxyethoxy)-5,6,7,8-tetrahydronaphth-2-yl]prop-2-yn-1-ol, which will be used for Example 5.18 g (48 mmol) of 1-[5,5,8,8-tetramethyl-4-(2-ethoxyethoxy)-5,6,7,8-tetrahydronaphth-2-yl]prop-2-yn-1-ol (R)-acetate are thus dissolved in 500 mL of a 2% solution of K2CO3 in methanol and the medium is stirred for 3 hours. The reaction medium is then treated with 0.01N hydrochloric acid solution and extracted with ethyl acetate. The residue obtained is purified by chromatography (eluent: 8/2 heptane/EtOAc). A colorless oil is obtained (m=15 g, yield=41%).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[Cl:16][C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:20][NH:21][CH2:22]CO.[C:29]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.Cl>O1CCCC1.C(OCC)(=O)C>[Cl:16][C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:20][N:21]1[CH2:29][CH2:3][O:1][CH:2]([CH2:4][N:5]2[C:6](=[O:15])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]2=[O:14])[CH2:22]1
Reactant: OCCNCc1ccc(Cl)c(Cl)c1
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 66 °C
Reaction time: 14 h

Procedure:
To a solution of 2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione (N-(2,3-epoxypropyl)phthalimide) (2 g) in tetrahydrofuran (4 ml) was added 2-[(3,4-dichlorobenzyl)amino]ethanol (2.16 g) with stirring, under a nitrogen atmosphere. The mixture was heated to 66° C. for 22 h, then cooled to 0° C. A further portion of tetrahydrofuran (10 ml) was added, followed by triphenylphosphine (2.88 g). Diisopropyl azodicarboxylate (2.2 g) was then added over 10 min. The mixture was stirred at 0° C. for a further 30 min, and at room temperature for 14 h. To the crude solution was added ethyl acetate (100 ml), then 2M aqueous hydrochloric acid (250 ml). The resulting white precipitate was isolated by filtration, and dried in vacuo to give the title compound as its white crystalline hydrochoride salt (2.01 g). This was partitioned between 8% aqueous sodium bicarbonate (200 ml) and ethyl acetate (50 ml). The organic phase was separated, dried over magnesium sulfate and the solvent evaporated in vacuo to give a solid. Dichloromethane (20 ml) was added to the residue and the solvent again evaporated in vacuo to give the title compound as a white solid (1.1 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CCCBr
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(F)c1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A mixture of 3-fluorophenol (6.00 g, 53.5 mmol), ethyl 4-bromobutanoate (15.70 g, 80.5 mmol) and Cs2CO3 (26.20 g, 80.4 mmol) in DMF (25 mL) under N2 was refluxed overnight. The mixture was then cooled to rt and 150 mL of water was added. The resulting mixture was extracted with DCM (100 mL×2) and the combined organic phases were washed with brine (100 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=10:1) to give the title compound as colorless oil (12.0 g, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[F:9][C:10]([F:15])([F:14])[CH:11]1[O:13][CH2:12]1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:12][CH:11]([OH:13])[C:10]([F:15])([F:14])[F:9])[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)C1CO1
Reactant: Nc1cccc(Br)c1
Product: OC(CNc1cccc(Br)c1)C(F)(F)F
Temperature: 70 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
EX-633A) 3-Bromoaniline (2.15 g, 12.5 mmol) and 1,1,1-trifluoro-2,3-epoxypropane (1.0 g, 8.9 mmol) were placed in a sealed vial, heated to 70° C. and stirred for 1 h under an atmosphere of nitrogen. The crude product was purified by flash column chromatography on silica gel eluting with CH2CH2:hexane (2:1) to give 2.11 g (84%) of the desired 3-[(3-bromophenyl)amino]-1,1,1-trifluoro-2-propanol product as a light amber oil, 98% pure by HPLC analysis. MS m/z=284/286 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Br:15][CH2:16][S:17](Br)(=[O:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Br:15][CH2:16][S:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:19])=[O:18]
Reactant: O=S(=O)(Br)CBr
Reactant: CCCCCCC=CCCCCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCC=CCCCCCCS(=O)(=O)CBr
Yield: 100.7 %

Procedure:
A mixture of 7-tetradecene (3.92 g) and bromomethanesulfonyl bromide (7.14 g) in methylene chloride (8 mL) was irradiated at -15° C. with an ultraviolet lamp for 2 hours. A small amount of solid potassium carbonate was added and then removed by filtration. The reaction mixture was diluted with methylene chloride (100 mL) and triethylamine (3.0 g) was added. The reaction mixture was heated on a steam bath for 1 hour. The reaction mixture was washed with dilute HCl and water. The methylene chloride layer was separated, dried over anhydrous magnesium sulfate and the methylene chloride removed in vacuo to give 7.1 g (100% yield) of oily 7-tetradecenyl bromomethyl sulfone which was characterized by IR and NMR spectroscopy.
Reaction SMILES: [N:1]([O-])=O.[Na+].[I:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl.[OH2:16]>>[I:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:1]=[C:9]2[CH:10]=[O:16]
Reactant: O=N[O-]
Reactant: Ic1ccc2[nH]ccc2c1
Reactant: O
Agent: Cl
Agent: [Na+]
Product: O=Cc1n[nH]c2ccc(I)cc12
Reaction time: 8 h

Procedure:
1 g of sodium nitrite (27.6 g, 400 mmol) is added portionwise, under argon, to a suspension of 5-iodoindole (9.722 g, 40 mmol) in water, followed dropwise by a 6N HCl solution (59 ml). The temperature of the reaction mixture is maintained below 15° C. and the reaction mixture is then left at ambient temperature overnight, with vigorous stirring. The nitrous vapours are expelled under a stream of argon, and the reaction mixture is then filtered. Washing the solid with H2O followed by purification on silica gel (600 g), elution being carried out according to an elution gradient from CH2Cl2 to a CH2Cl2/EtOAc (9/1) mixture, makes it possible to isolate 1.37 g of product in the form of a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:34]([CH3:42])[CH2:35][CH:36]([CH3:41])[CH2:37][CH2:38][CH:39]=[CH2:40])[C:10]([N:12]1[CH2:16][C@H:15]([O:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([O:28][CH2:29][CH3:30])=[CH:20][N:19]=2)[CH2:14][C@H:13]1[C:31](O)=[O:32])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:77][C@:78]1([C:83]([NH:85][S:86]([CH:89]2[CH2:91][CH2:90]2)(=[O:88])=[O:87])=[O:84])[CH2:80][C@H:79]1[CH:81]=[CH2:82]>ClCCl>[CH:89]1([S:86]([NH:85][C:83]([C@@:78]2([NH:77][C:31]([C@@H:13]3[CH2:14][C@@H:15]([O:17][C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C:21]([O:28][CH2:29][CH3:30])=[CH:20][N:19]=4)[CH2:16][N:12]3[C:10](=[O:11])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[C@H:34]([CH3:42])[CH2:35][CH:36]([CH3:41])[CH2:37][CH2:38][CH:39]=[CH2:40])=[O:32])[CH2:80][C@H:79]2[CH:81]=[CH2:82])=[O:84])(=[O:88])=[O:87])[CH2:91][CH2:90]1
Reactant: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc2ncc(OCC)c3ccccc23)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc2ncc(OCC)c3ccccc23)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a solution of (2S,4R)-1-((3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-((4-ethoxyisoquinolin-1-yl)oxy)pyrrolidine-2-carboxylic acid (600 mg, 1.0 mmole) in dichloromethane (10 mL) was added DIPEA (0.87 mL, 5 mmole), HATU (380 mg, 1.0 mmole) followed by (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide hydrochloride (prepared according to the procedure described in WO 03/099274) (457 mg, 1.1 mmole) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mass was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired product tert-butyl ((3R)-1-((2S,4R)-2-(((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-((4-ethoxyisoquinolin-1-yl)oxy)pyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate (500 mg, 61%) as off-white solid. MS: MS m/z 797.2 (M++1).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:38]2[CH2:50][CH2:49][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[CH:48]=[C:40]3[C:39]2=[O:51])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][C@@H:26]3[CH3:35])=[CH:21][N:20]=2)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:38]2[CH2:50][CH2:49][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[CH:48]=[C:40]3[C:39]2=[O:51])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:32][O:33][CH2:34]4)[CH2:27][C@@H:26]3[CH3:35])=[CH:21][N:20]=2)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cnc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CN(C2COC2)CCN1c1cnc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4=O)c3CO)cn(C)c2=O)cn1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 21.9 %

Procedure:
A mixture of 228a (50 mg, 0.070 mmol) and lithium hydroxide (43 mg, 1.8 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 35° C. for 30 mins. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 228 (10 mg, 21%). MS-ESI: [M+H]+ 652.3. 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.48 (d, J=4.5 Hz, 1H), 8.39 (s, 1H), 8.34 (s, 1H), 7.84 (s, 1H), 7.48 (s, 1H), 7.34 (d, J=5.0 Hz, 1H), 6.58 (s, 1H), 4.94 (bs, 1H), 4.56-4.55 (m, 2H), 4.49-4.47 (m, 1H), 4.42-4.36 (m, overlap, 4H) 4.25-4.17 (m, 2H), 4.13-4.10 (m, 1H), 3.86-3.76 (m, 2H), 3.60 (s, 3H), 3.39-3.37 (m, 1H), 3.01-2.96 (m, 1H), 2.78-2.76 (m, 1H), 2.62-2.57 (m, overlap, 3H), 2.50-2.47 (m, 2H), 2.10-2.07 (m, 1H), 1.94-1.90 (m, 1H), 1.80-1.78 (m, 2H), 1.70-1.69 (m, 2H), 1.12 (d, J=6.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][C:21]3[CH:30]=[N:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([Cl:31])[CH:27]=4)[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O:35]CC)=[O:34].[OH-].[Na+].C(O)C>C1COCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:32])[NH:20][C:21]3[CH:30]=[N:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([Cl:31])[CH:27]=4)[N:22]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([OH:35])=[O:34]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cnc5cc(Cl)ccc5n4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(Nc1cnc2cc(Cl)ccc2n1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 2 h
Yield: 82.3 %

Procedure:
Ethyl 6-chloro-7-(4-(6-chloroquinoxalin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (540 mg, 1.00 mmol) was diluted with THF (8 mL) followed by the addition of NaOH (5015 μL, 5.02 mmol) and ethanol (4 mL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 0.5 M HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was triturated with DCM to provide the desired product (420 mg, 0.823 mmol, 82.1% yield). MS (ESI)=510.1 (M+1).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH:16]=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.C(O)C.[OH-].[Na+]>O>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH2:15][O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCC=C(c2ccccc2)c2cccc(OC)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cccc(C(=CCOCCN2CCC[C@@H](C(=O)O)C2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 107.1 %

Procedure:
(R)-N-(2-(3-(3-Methoxyphenyl)-3-phenyl-2-propen-1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester (25 g, 59 mmol) was dissolved into 96% ethanol (275 ml) and a 12 N sodium hydroxide solution (22 ml) was added. The reaction mixture was stirred at room temperature for 3.5 h. The solvent was evaporated in vacuo and dichloromethane was added (250 ml). A concentrated hydrochloric acid solution (29.5 ml) was added with cooling of the reaction vessel in an ice-bath. The phases were separated and the organic phase was dried (Na2SO4). The solvent was evaporated in vacuo to give a residue which was dissolved into water (250 ml). The aqueous solution was extracted with toluene (3×50 ml) and diethyl ether (50 ml). The organic extracts were discarded and from the aqueous phase water was evaporated in vacuo to give 25 g (98%) of the title compound as an oil.
Reaction SMILES: B(Cl)(Cl)Cl.C(Cl)Cl.[Cl:8][C:9]1[N:14]2[N:15]=[CH:16][N:17]=[C:13]2[C:12]([CH2:18][CH2:19][O:20]CC)=[C:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:10]=1.O>C(Cl)(Cl)Cl>[Cl:8][C:9]1[N:14]2[N:15]=[CH:16][N:17]=[C:13]2[C:12]([CH2:18][CH2:19][OH:20])=[C:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:10]=1
Reactant: CCOCCc1c(-c2ccccc2)nc(Cl)n2ncnc12
Agent: ClB(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: OCCc1c(-c2ccccc2)nc(Cl)n2ncnc12

Procedure:
Under non-aqueous conditions 200 ml of a mixture of boron trichloride (0.2 mol) and methylene chloride (1 mol) is added over a period of 20 minutes with vigorous stirring to a solution containing 30 g of 5-chloro-8-(2-ethoxyethyl)-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidine (0.1 moles) dissolved in 300 ml of chloroform. The resulting reaction mixture is stirred at room temperature for 3 hours. To the reaction mixture is added 400 ml of water and the resulting mixture is stirred for 1.5 hours and then allowed to stand at room temperature. The aqueous and organic layers are separated and the organic layer is dried over sodium sulfate, filtered and evaporated yielding a residue. The residue is chromatographed on silica gel and recrystallized from diethyl ether to yield 5-chloro-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidine-8-ethanol having the structural formula ##STR21## and the azido tautomer thereof as a white solid having a melting point of 104°-105° C. and the following elemental analysis:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:47][C:48]1[CH:49]=[C:50]2[C:54](=[CH:55][CH:56]=1)[NH:53][C:52]([CH:57]([CH3:60])[CH2:58][OH:59])=[CH:51]2>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:47][C:48]4[CH:49]=[C:50]5[C:54](=[CH:55][CH:56]=4)[NH:53][C:52]([CH:57]([CH3:60])[CH2:58][OH:59])=[CH:51]5)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CC(CO)c1cc2cc(N)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(CO)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 51.2 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (0.10 g, 0.49 mmol) in acetonitrile (2.0 mL) were added HBTU (0.185 g, 0.49 mmol) and Et3N (205 μL, 1.47 mmol) at room temperature. The mixture was allowed to stir at room temperature for 10 minutes before a slurry of 2-(5-amino-1H-indol-2-yl)propan-1-ol (0.093 g, 0.49 mmol) in acetonitrile (2.7 mL) was added. After addition, the reaction mixture was stirred at room temperature for 5.5 h. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The organic layer was washed with 1 N HCl (1×3 mL) and saturated aqueous NaHCO3 (1×3 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel (ethyl acetate/hexane=13/7) to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(1-hydroxypropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (0.095 g, 51%). 1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.38 (s, 1H), 7.55 (s, 1H), 7.14 (d, J=8.6 Hz, 1H), 7.02-6.90 (m, 4H), 6.06 (s, 1H) 6.02 (s, 2H), 4.76 (t, J=5.3 Hz, 1H), 3.68-3.63 (m, 1H), 3.50-3.44 (m, 1H), 2.99-2.90 (m, 1H), 1.41-1.38 (m, 2H), 1.26 (d, J=7.0 Hz, 3H), 1.05-1.02 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.O=[C:16]([CH3:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19].[NH2:23]/[C:24](/[CH3:28])=[CH:25]\[C:26]#[N:27].C(O)(=O)C>CC(O)C>[C:26]([C:25]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([CH3:22])[NH:23][C:24]=1[CH3:28])#[N:27]
Reactant: C/C(N)=C/C#N
Reactant: COC(=O)CC(C)=O
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C#N)C1c1cccc2c(=O)cc(C)oc12
Temperature: 25 °C

Procedure:
100 mg (0.53 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 61.7 mg (0.53 mmol) of methyl 3-oxobutanoate, 43.6 mg (0.53 mmol) of 3-aminocrotononitrile and 31.9 mg (0.53 mmol) of acetic acid in 5 ml of 2-propanol and heated under reflux under argon for 4 h. After cooling to room temperature, the crystallized product is filtered off and washed with 2-propanol and, diethyl ether. 97 mg (52% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.Br[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(Cl)(Cl)Cl>[O:13]([CH2:12][CH2:11][NH:9][C:4]1[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=1)[O:2][CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccccc1N
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: COc1ccccc1NCCOc1ccccc1
Yield: 52.6 %

Procedure:
A suspension of 6.2 g (50 mmol) o-anisidine M10, 12.1 g (60 mmol) β-bromophenetole M20 and 8.3 g (60 mmol) K2CO3 in 25 ml acetonitrile was heated at reflux for 18 hours. The mixture was cooled, diluted with 100 ml CHCl3 and washed with 100 ml water and 100 ml saturated NaCl. The organic layer was dried over Na2SO4. The solvent was evaporated to give 14.5 g crude oil. This oil was purified by a plug packed with 60 g silica gel 100 with cyclohexane as eluant, wherein 6.4 g pure product were obtained (yield: 51%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:10].[OH-].[K+].Br[CH2:14][CH2:15][CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(Cl)Cl>CC(C)=O>[Si:18]([O:17][CH2:16][CH2:15][CH2:14][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:10])([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: Nc1nc2ccccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCn1c(N)nc2ccccc21
Reaction time: 1 h
Yield: 17.3 %

Procedure:
1H-Benzoimidazol-2-ylamine (1 g, 7.5 mmol) was dissolved in acetone (30 mL) and powdered potassium hydroxide (2.12 g, 37.5 mmol) was added. The reaction was allowed to stir for several minutes at room temperature before (3-bromopropoxy)(tert-butyl)dimethylsilane (1.75 mL, 7.5 mmol) was added. After 1 hour, methylene chloride was added and the mixture was washed with water, brine and dried over magnesium sulfate. Upon concentration the crude product was dissolved in methylene chloride and purified by combiflash chromatography, methylene chloride to methylene chloride 6% MeOH gradient, to give 1-(3-(tert-butyldimethylsilyloxy)propyl)-1H-benzo[d]imidazol-2-amine (0.400 g, 1.3 mmol).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][S:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[OH:11]O>C(O)(=O)C>[O:4]1[C:5]2([CH2:10][CH2:9][S:8](=[O:11])[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: OO
Reactant: C1COC2(CCSCC2)O1
Solvent: CC(=O)O
Product: O=S1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A room temperature mixture of 13.8 g of product from Example 392 dissolved in 100 ml of acetic acid is treated, dropwise over 20 minutes, with 9.0 mlof 30% hydrogen peroxide. The reaction mixture is stirred at room temperature for 1 hour, concentrated in vacuo at 50° C., and extracted with ethyl acetate. The organic layer is washed 2 X with saturated sodium bicarbonate, water and saturated sodium chloride, dried and concentrated in vacuo. The aqueous washes are combined and concentrated in vacuo to about 25 ml. The residue is saturated with solid potassium carbonate and extracted 2 X with 200 ml of ethyl acetate. The organic phase is concentrated in vacuo to a solid which is triturated withhexane and collected to give 13.1 g of the desired product.