Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.Cl[CH2:12][C:13]([CH3:15])=[CH2:14].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C1(C)C=CC=CC=1>[CH3:14][C:13](=[CH2:12])[CH2:15][O:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:9][CH3:10]
Reactant: C=C(C)CCl
Reactant: COc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C=C(C)COc1cc(Br)ccc1OC
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 5-bromo-2-methoxyphenol (17.8 g), 3-chloro-2-methyl-1-propene (13.0 ml), potassium carbonate (18.2 g), and DMF (150 ml) was stirred at 80° C. for 2 hours. The mixture was diluted with toluene, washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off to give Compound IIa-a (22.2 g, 98.4%) as a colorless oily substance.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][C:23]=3[F:24])[N:20]=[CH:19][CH:18]=[CH:17]4)([OH:13])[CH3:12])=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:30]([O:32]CC)=[CH2:31])CCC.Cl.O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:24][C:23]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[N:20]2)=[CH:15][C:14]=1[C:11]([C:8]1[N:6]2[N:7]=[C:2]([C:30](=[O:32])[CH3:31])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)([OH:13])[CH3:12]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(O)(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2ncc(C(C)(O)c3cc4cccnc4cc3F)n2n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
In a flask was charged with tetrakis-(triphenylphosphine)-palladium (51 mg, 0.044 mmol) under nitrogen. A solution of 1-(6-chloroimidazo[1,2-b]pyridazin-3-yl)-1-(7-fluoroquinolin-6-yl)ethanol (150 mg, 0.44 mmol) in DMF (10 mL) was added. The system was purged with nitrogen gas three times and tributyl-(1-ethoxy-vinyl)-stannane (0.16 ml, 0.46 mmol) was added. The temperature was increased to 100° C. and stirred overnight. The reaction mixture was cooled to room temperature, 3N HCl was added and the mixture was stirred for additional 4 hrs. Water was added and the mixture was then extracted with EtOAc, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (3% to 10% MeOH in CH2Cl2) to afford 70 mg (yield: 41%) title compound. LCMS (method B): [MH]+=351, tR=2.01 min.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[CH2:21][CH2:22][CH3:23])C.Cl.C(=O)([O-])[O-].[K+].[K+]>O.ClCCl>[CH2:21]([C:9]1[N:8]([CH2:7][CH2:6][CH2:5][CH:4]=[O:3])[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=1)[CH2:22][CH3:23]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(OCC)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCCc1nc2cnc3ccccc3c2n1CCCC=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 113.3 %

Procedure:
1-(4,4-diethoxybutyl)-2-propyl-1H-imidazo[4,5-c]quinoline (25.3 g, 71.2 mmol) was added to a solution of concentrated hydrochloric acid (35 mL) and water (35 mL) cooled to 0° C. and the reaction mixture was allowed to warm to ambient temperature and was stirred for 30 minutes. The reaction mixture was diluted with water (100 mL) and dichloromethane (200 mL) and the pH of the reaction mixture was slowly made basic with addition of potassium carbonate. The aqueous and organic layers were separated and the organic layer was dried over potassium carbonate, filtered, and concentrated to afford 22.7 g of 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde.
Reaction SMILES: N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1C[C@H](OC2C=CC=CN=2)CN1C(C1C=CC=CC=1)C1C=CC=CC=1)O.[NH2:39][C@@H:40]([CH2:68][C:69]1[CH:74]=[C:73]([F:75])[CH:72]=[C:71]([F:76])[CH:70]=1)[C@@H:41]([C@H:43]1[CH2:47][C@@H:46]([O:48][C:49]2[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=2)[CH2:45][N:44]1C(C1C=CC=CC=1)C1C=CC=CC=1)[OH:42].[C:77]([NH:80][C@:81]1([C@@H:130]([CH2:132][CH3:133])[CH3:131])[CH2:85][CH2:84][N:83]([C@@H:86]([CH2:121][CH2:122][C:123]2[CH:128]=[CH:127][CH:126]=[CH:125][CH:124]=2)[C:87](N[C@@H](CC2C=C(F)C=C(F)C=2)[C@@H]([C@H]2CCCCN2C(C2C=CC=CC=2)C2C=CC=CC=2)O)=[O:88])[C:82]1=[O:129])(=[O:79])[CH3:78].[Li+].[OH-]>CCO.O>[C:77]([NH:80][C@:81]1([C@@H:130]([CH2:132][CH3:133])[CH3:131])[CH2:85][CH2:84][N:83]([C@@H:86]([CH2:121][CH2:122][C:123]2[CH:124]=[CH:125][CH:126]=[CH:127][CH:128]=2)[C:87]([NH:39][C@@H:40]([CH2:68][C:69]2[CH:74]=[C:73]([F:75])[CH:72]=[C:71]([F:76])[CH:70]=2)[C@H:41]([OH:42])[C@H:43]2[CH2:47][C@@H:46]([O:48][C:49]3[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=3)[CH2:45][NH:44]2)=[O:88])[C:82]1=[O:129])(=[O:79])[CH3:78]
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2CCCCN2C(c2ccccc2)c2ccccc2)C1=O
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@@H](Oc2cccnc2)CN1C(c1ccccc1)c1ccccc1
Agent: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@H](Oc2ccccn2)CN1C(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@@H](Oc3cccnc3)CN2)C1=O
Temperature: 25 °C

Procedure:
Step 13 (B): (1S,2S)-2-amino-1-((2R,4R)-1-benzhydryl-4-(pyridin-3-yloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)propan-1-ol. To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((2R,4R)-1-benzhydryl-4-(pyridin-3-yloxy)pyrrolidin-2-yl)oxazolidin-2-one (Step 13 (A), 119 mg, 0.22 mmol) in EtOH (10 mL) was added a solution of LiOH (106 mg, 4.4 mmol) in H2O (3 mL). This reaction mixture was stirred at reflux for 4 h. After cooling down to rt, the mixture was concentrated to remove EtOH and H2O was added followed by 1N HCl solution and pH 7 buffer. The mixture was extracted with ethyl acetate and the organic phase was washed with sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo. Flash chromatography (silica gel, 0-10% MeOH/chloroform) gave 25.9 mg of the title compound as an opaque oil:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][NH:10][C:4]=2[CH:3]=1.[CH3:15][O:16][CH2:17][C@@H:18]([NH:25][C:26]([NH2:28])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:15][O:16][CH2:17][C@@H:18]([NH:25][C:26]([NH:28][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][NH:10][C:4]=2[CH:3]=1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: FC(F)(F)c1n[nH]c2cc(Cl)ncc12
Reactant: COC[C@@H](NC(N)=O)c1ccccc1
Product: COC[C@@H](NC(=O)Nc1cc2[nH]nc(C(F)(F)F)c2cn1)c1ccccc1

Procedure:
In a manner similar to that described in Example 30 (Step 1), 6-chloro-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine was reacted with (S)-1-(2-methoxy-1-phenylethyl)urea (BrettPhos precatalyst, KOtBu, dioxane, 90° C., overnight) to provide 1-[(1S)-2-methoxy-1-phenylethyl]-3-[3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl]urea. MS ESI calc'd. for C17H16F3N5O2[M+1]+ 380, found 380.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=2)[C:16]1=[O:27])C1C=CC=CC=1>CO>[OH:8][NH:9][C:10](=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=2)[C:16]1=[O:27]
Reactant: COc1ccc2c(c1)CCC(CCCCC(=O)NOCc1ccccc1)C2=O
Solvent: CO
Product: COc1ccc2c(c1)CCC(CCCCC(=O)NO)C2=O

Procedure:
5-(6-methoxy-1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl)-pentanoic acid (2b) is prepared from 6-methoxy-1-oxo-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid ethyl ester (2a) (Basu, B., et al., Synth. Commun., 11, 10, 1981, 803-810) in an analogous manner to that described for 1b in example 1. 6.6 g (24.3 mmol) 1b are dissolved in 140 mL of CH2Cl2. To this solution is added sequentially 3.3 mL triethylamine, 6.9 g bis-(2-oxo-3-oxazolidinyl)-phosphorylchlorid, 3.0 g O-benzylhydroxylamine and another 10.2 mL triethylamine. After stirring over night the solution is washed with 2N HCl, then sat. NaCl sol., and evaporated. On treating with diethylether, 8.5 g 5-(6-Methoxy-1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl)-pentanoic acid benzyloxy-amide (2c) is obtained as bright crystalls. Hydrogenation of 0.5 g of 2c in Methanol with Pd/BaCO3/Pb as a catalyst yields, after evaporation and treating with diethylether, 0.3 g of the title compound, MP 118-120° C.
Reaction SMILES: C(OC(=O)[C:5]([CH2:11][C:12]1([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])[CH2:14][CH2:13]1)([OH:10])[C:6]([F:9])([F:8])[F:7])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:9][C:6]([F:7])([F:8])[C:5](=[O:10])[CH2:11][C:12]1([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])[CH2:13][CH2:14]1
Reactant: CCOC(=O)C(O)(CC1(c2cc(F)ccc2OC)CC1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C1(CC(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 88.3 %

Procedure:
To a chilled (0° C.) solution of 400 mg (1.14 mmol) of 3,3,3-trifluoro-2-[1-(5-fluoro-2-methoxyphenyl)cyclopropylmethyl]-2-hydroxypropionic acid ethyl ester in 5 mL of anhydrous THF was added 98 mg (2.58 mmol) of lithium aluminum hydride in several portions. The cold bath was then removed and the mixture was stirred at room temperature. After 4.5 hours, the mixture was cooled in an ice water bath and cautiously quenched with water, dried over magnesium sulfate, and filtered through diatomaceous earth, washing with EtOAc to afford 278 mg (78%) of title compound which was used without further purification. The filter cake was partitioned between 15 mL of 1 N aqueous hydrochloric acid and extracted with three 10 mL portions of EtOAc. The combined organic layers were washed with two 10 mL portions of 1 N aqueous hydrochloric acid, 10 mL of brine, and two 10 mL portions of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated to afford an addition 32 mg (8.9%) of 3,3,3-trifluoro-2-[1-(5-fluoro-2-methoxyphenyl)cyclopropylmethyl]propane-1,2-diol.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1.[N:21]#[C:22][NH2:23].[OH:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26].C(O)(C(F)(F)F)=O>C1COCC1>[OH:27][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:26])=[O:24].[C:22](=[NH:21])([O:15][CH2:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([C:2]([F:19])([F:20])[F:1])[CH:4]=2)=[CH:12][CH:11]=1)[NH2:23]
Reactant: N#CN
Reactant: OCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)OCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 55 °C
Yield: 59.7 %

Procedure:
To a solution of 2-(4-(3-(trifluoromethyl)phenoxy)phenyl)ethanol (1.395 g, 4.94 mmol) and cyanamide (0.249 g, 5.93 mmol) in THF (15 mL) was added triflic acid (0.527 mL, 5.93 mmol) under argon. The mixture was heated at 55° C. for 3 h. The mixture was purified by a reverse phase biotage with TFA affording the title compound (1.4 g, 59.8% yield). LCMS: rt=1.23 min, [M+H+]=325
Reaction SMILES: C([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]2[CH2:20][CH2:21][N:22](CC3C=CC=CC=3)[CH2:23][CH2:24][C:12]=12)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH2:24]1[C:12]2=[C:11]([CH2:10][CH2:9][NH2:8])[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]2[CH2:20][CH2:21][NH:22][CH2:23]1
Reactant: c1ccc(CNCCc2c3n(c4ccccc24)CCN(Cc2ccccc2)CC3)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: NCCc1c2n(c3ccccc13)CCNCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
A solution of N-benzyl-2-(3-benzyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-11-yl)-1-ethanamine (195 mg, 0.48 mmol) in methanol (10 mL) is treated with 10% palladium on carbon (40 mg) and ammonium formate (210 mg, 3.3 mmol) followed by heating to reflux. After 18 hrs, the reaction is cooled to rt, filtered through celite, and concentrated to give a crude yellow oil. This material is purified by LC (230-400 silica gel) eluting with 20:2.5:77.5 methanol/ammonuim hydroxide/dichloromethane to afford 51 mg (47%) of 2-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-11-yl)-1-ethanamine as a colorless oil that solidified, mp 77-80° C. MS (EI) m/z 229 (M+); % Water (KF): 0.94; Anal. Calculated for C14H19N3.0.94 H2O: C, 72.64; H, 8.38; N, 18.15. Found: C, 72.66; H, 8.32; N, 18.03.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]1[CH:18]=[CH:19][C:20](O)=[C:21]([C:23](=[O:25])[CH3:24])[CH:22]=1>N1C=CC=CC=1.C(OCC)C>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:20]1[CH:19]=[CH:18][C:17]([F:16])=[CH:22][C:21]=1[C:23](=[O:25])[CH3:24])(=[O:8])=[O:9]
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)c1cc(F)ccc1OS(=O)(=O)C(F)(F)F
Reaction time: 8 h
Yield: 101.4 %

Procedure:
Trifluoromethanesulfonic anhydride (8.6 mL, 51 mmol) was added dropwise at 0° C. to a stirring solution of 5′-fluoro-2′-hydroxy-acetophenone (6.4 g, 41 mmol) in pyridine (62 mL). The reaction was stirred overnight from 0° C. to ambient temperature. The reaction solution was diluted with diethyl ether (500 mL). The organic layer was washed with 1 N aqueous hydrochloric acid (1×300 mL), followed by a saturated, aqueous sodium chloride solution (2×300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a maroon-colored liquid (11.9 g, 100% ). The product was further purified by Kugel-Rohr distillation to afford a yellow oil that solidified upon standing.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[CH2:11]=O.Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH2:11][O:10][CH2:9][CH2:8]2
Reactant: OCCc1cccc(Cl)c1
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc2c(c1)CCOC2
Reaction time: 8 h
Yield: 88.6 %

Procedure:
2-(3-Chlorophenyl)ethanol (48.2 g) and paraformaldehyde (10.8 g) were mixed and warmed to 70° on an oil bath. A stream of hydrogen chloride gas was passed vigorously through the suspension for about 7 hr. The reaction mixture was then allowed to stand at room temperature overnight. Aqueous sodium hydroxide solution (100 g/100 ml) was added cautiously to the reaction mixture. After the initial reaction subsided the rest of the alkali solution was run in fast and the resulting mixture was heated at reflux on an oil bath for 2 hr. The reaction mixture was cooled and extracted into ether (3×100 ml). The ether layer was dried (sodium sulphate) and evaporated in vacuo to give the 6-chloroisochroman as an oil (46 g), which was purified by distillation in vacuo (25.1 g, b.pt. 76°-80°/0.6 mmHg), characterised by its nmr spectrum.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[C:10]([O:17][CH2:18][C@@H:19]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=1[OH:38]>>[CH2:1]([N:8]1[C:12]([C:13](=[O:15])[NH:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=2[OH:38])=[C:11]([CH3:16])[C:10]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:23])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH3:20])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(OC[C@H](C)NC(=O)OC(C)(C)C)nn(Cc2ccccc2)c1C(=O)O
Reactant: Nc1ccc(O)cc1O
Agent: Cl
Product: Cc1c(OC[C@H](C)NC(=O)OC(C)(C)C)nn(Cc2ccccc2)c1C(=O)Nc1ccc(O)cc1O

Procedure:
Using 1-benzyl-3-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)-4-methyl-1H-pyrazole-5-carboxylic acid and 4-aminobenzene-1,3-diol hydrochloride, and in the same manner as in Example 2, step C, the title compound was obtained.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:27]([CH3:38])[CH:26]=1.C(N(CC)C(C)C)(C)C>CC#N>[CH2:1]([N:5]([CH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:27]([CH3:38])[CH:26]=1)[C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)COc1ccc(CBr)cc1C
Reactant: CCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a solution of N-butyl-N-[2-methyl-4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (102 mg, 0.33 mmol) in anhydrous MeCN (8 mL) under nitrogen at room temperature was added ethyl [4-(bromomethyl)-2-methylphenoxy]acetate (95.3 mg, 0.33 mmol) and N,N-diisopropyethylamine (57.8 μL, 0.33 mmol). The resultant solution was heated to reflux and stirred for 3 h. The reaction mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was partitioned between CHCl3 (2×10 mL) and water (10 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by Biotage™ chromatography (40 g Silica column) eluted with 1:99–1:49 EtOAc:cyclohexane afforded the title compound as a colourless oil (110 mg).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1C(=O)C2C(=CC=CC=2)C1=O)=[N+:2]=[N-:3].NN.O>C(O)C>[N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccccc1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=Nc1ccccc1N
Reaction time: 0.25 h
Yield: 25.6 %

Procedure:
To a suspension of the of 2-(2-azido-phenyl)-isoindole-1,3-dione (373 mg, 1.4 mmol) in ethanol (10 mL) was added hydrazine (140 μL, 4.24 mmol) followed by stirring for 15 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate (3×25 mL). The combined extracts were washed with water and brine and were dried over magnesium sulfate. Filtration and concentration in vacuo gave a residue which was purified via radial chromatography (1 mm plate, 10% 5ethyl acetate/hexanes to 33% ethyl acetate/hexanes gradient elution) to give 48 mg (25%) of 2-azidophenylamine as a solid: 1H NMR (300 MHz, DMSO-d6) δ 6.98 (m, 1H), 6.86 (m, 1H), 6.66-6.55 (m, 2H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li:10]CCCC>CCCCCCC>[CH:1]1([Li:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C1=Cc2ccccc2C1
Reactant: [Li]CCCC
Solvent: CCCCCCC
Product: [Li]C1C=Cc2ccccc21
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To distilled indene (15.0 g, 129 mmol) in heptane (200 mL) was added BuLi (82 mL, 131 mmol, 1.6 M in hexanes) at room temperature. The resulting reaction mixture was stirred overnight. The mixture was filtered and the filter cake washed with heptane (3×30 mL) to give indenyllithium (15.62 g, 99% yield). Indenyllithium (6.387 g, 52.4 mmol) was added as a solid over 5 minutes to a stirred solution of C6F5CH2—Br (13.65 g, 52.3 mmol) in toluene (100 mL) at room temperature. The reaction mixture was heated to 50° C. and stirred for 4 h. The product mixture was filtered and washed with toluene (3×20 mL). The combined filtrates were evaporated to dryness to afford 1-C6F5CH2-indene (13.58 g, 88%). To a stirred slurry of TiCl40.2THF (1.72 g, 5.15 mmol) in toluene (15 mL) was added solid (t-Bu)3P═N—Li (1.12 g, 5 mmol) at room temperature. The resulting reaction mixture was heated at 100° C. for 30 min and then allowed to cool to room temperature. This mixture containing ((t-Bu)3P═N)TiCl3 (1.85 g, 5 mmol) was used in the next reaction. To a THF solution (10 mL) of 1-C6F5CH2-indene (1.48 g, 5 mmol) cooled at −78° C. was added n-butyllithium (3.28 mL, 5 mmol, 1.6 M in hexanes) over 10 minutes. The resulting dark orange solution was stirred for 20 minutes and then transferred via a double-ended needle to a toluene slurry of ((t-Bu)3P═N)TiCl3 (1.85 g, 5 mmol). The cooling was removed from the reaction mixture which was stirred for a further 30 minutes. The solvents were evaporated to afford a yellow pasty residue. The solid was re-dissolved in toluene (70 mL) at 80° C. and filtered hot. The toluene was evaporated to afford pure (1-C6F5CH2—Indenyl)((t-Bu)3P═N)TiCl2 (2.35 g, 74%).
Reaction SMILES: C([O:3][P:4]([CH2:9][O:10][CH2:11][CH2:12][CH:13]([O:16][N:17]1[CH:25]=[N:24][C:23]2[C:22](=[O:26])[NH:21][C:20]([NH2:27])=[N:19][C:18]1=2)[CH2:14][OH:15])([O:6]CC)=[O:5])C.Br[Si](C)(C)C>CN(C)C=O>[OH:15][CH2:14][CH:13]([O:16][N:17]1[CH:25]=[N:24][C:23]2[C:22](=[O:26])[NH:21][C:20]([NH2:27])=[N:19][C:18]1=2)[CH2:12][CH2:11][O:10][CH2:9][P:4]([OH:6])([OH:5])=[O:3]
Reactant: CCOP(=O)(COCCC(CO)On1cnc2c(=O)[nH]c(N)nc21)OCC
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Product: Nc1nc2c(ncn2OC(CO)CCOCP(=O)(O)O)c(=O)[nH]1
Temperature: 20 °C
Reaction time: 3 h
Yield: 24.9 %

Procedure:
A solution of 9-[4-(diethoxyphosphorylmethoxy)-1-hydroxybut-2-oxy]guanine (95 mg, 0.23 mmol) in N,N-dimethylformamide (5 ml) was treated with bromotrimethylsilane (0.62 ml, 4.6 mmol) and stirred at 20° C. for 3 h. The reaction mixture was evaporated in vacuo, the residue dissolved in water and passed down reverse- phase silica eluting with water. Evaporation of the appropriate fractions in vacuo gave a white foamy solid which was recrystallised from acetone-water, affording 9-[1-hydroxy-4-(phosphonomethoxy)but-2-oxy]guanine (20 mg, 24%) as a white solid m.p. 188°-192° C. νmax (KBr) 3400, 3100, 1700, 1650 and 1600 cm-1 ; δH [(CD3)2SO] 1.85 (2H, m, HOCH2CHCH2), 3.30 (2H, br.s, D2O exchangeable, P(OH)2), 3.4-3.7 (6H,m, CH2OCH2P+CH2OH), 4.30 (1H, m, HOCH2CH), 5.0 (1H, br.s, D2O exchangeable, OH), 6.62 (2H, br.s, D2O exchangeable, NH2), 7.86 (1H, s, H-8); m/z (FAB+ve Ion), 372 (MNa+), 350 (MH+); Found: C, 33.97; H, 4.69; N, 20.11%; C10H16N5O7P requires C, 34.29; H, 4.62; N, 20.10%.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]\[CH3:4].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[C:6]1([N:5]2[CH2:4][CH:3]=[CH:2][CH2:1]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccccc1
Reactant: C/C=C\C
Solvent: Cc1ccccc1
Product: C1=CCN(c2ccccc2)C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
To a solution of 60.0 g of the cis-2-butene derivative solution prepared in Example 1 and 250 g of toluene in a round flask reactor, 149.0 g (1.6 mol) of aniline was added dropwise with stirring for 30 min. at 50° C. After 2 hours of stirring, the crystallized solid was removed by filtration; 42.0 g of 35% HCl (aq) was added to the filtrate, and then excess benzylamine hydrochloride was removed by filtration or extraction. After the solvent was evaporated under reduced pressure, 52.2 g of 1-phenyl-3-pyrroline (yield 90.0%) was obtained.