Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=[O:16])[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].[C:17]1(C)[CH:22]=CC(S(O)(=O)=O)=C[CH:18]=1.CO[C:30](OC)([CH3:32])[CH3:31]>ClC(Cl)C.ClCCl>[CH3:18][C:17]1([CH3:22])[O:8][C@H:3]([C@H:4]2[CH2:5][O:6][C:30]([CH3:32])([CH3:31])[O:7]2)[C@@H:2]([C:9]2[N:10]=[C:11]([C:14](=[O:16])[CH3:15])[NH:12][CH:13]=2)[O:1]1
Reactant: COC(C)(C)OC
Reactant: CC(=O)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)c1nc([C@H]2OC(C)(C)O[C@@H]2[C@H]2COC(C)(C)O2)c[nH]1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
1-[4-((1R,2S,3R)-1,2,3,4-Tetrahydroxy-butyl)-1H-imidazol-2-yl]-ethanone (18 g, 78.3 mmol) was suspended in dichloroethane (160 ml) and 2,2-dimethoxy propane (160 ml). 4-toluenesulfonic acid (3 g) was added and the mixture stirred at 70° C. for 18 hours. The reaction was diluted with dichloromethane and washed with water, 5% bicarbonate, brine and then dry loaded onto SiO2. Purification by flash chromatography (hexane/ethyl acetate) afforded 1-(4-((4S,4′R,5R)-2,2,2′,2′-tetramethyl-4,4′-bi(1,3-dioxolan)-5-yl)-1H-imidazol-2-yl)ethanone as a colorless oil (18.8 g, 60.6 mmol, 77%; M+H calc: 311.4, obs: 311.3).
Reaction SMILES: [NH2:1][OH:2].[CH2:3]([N:11]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:12][CH2:13][C:14](OCC)=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>C(OCC)C>[OH:2][NH:1][C:14](=[O:15])[CH2:13][CH2:12][N:11]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20]
Reactant: NO
Reactant: CCOC(=O)CCN(CCc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N(CCC(=O)NO)CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.8 %

Procedure:
Freshly prepared hydroxylamine reagent (20 mL; 20 mmol) was added to ethyl 3-[(phenethyl)-(4-methoxy-benzenesulfonyl)-amino]-propionate (3.30 g; 9.1 mmol) and the resulting mixture stirred for 18 h at room temperature. The mixture was poured into 1 N HCl (100 mL) and extracted with CH2Cl2 (2×100 mL). The combined extracts were washed with saturated aqueous NaCl (1×100 mL), dried over MgSO4, and evaporated under reduced pressure to give a crude gum. Trituration with diethyl ether afforded 2.23 g (65%) of the title compound as an off-white solid. 300 MHz 1H-NMR (DMSO-d6): δ 2.23 (t, 2H), 2.74 (m, 2H), 3.23 (m, 2H), 3.34 (m, 2H), 3.83 (s, 3H), 7.11 (d, 2H), 7.15-7.34 (m, 5H), 7.72 (d, 2H), 8.78 (s, 1H), 10.50 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[C:6]([S:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][CH2:19][CH2:18]3)[CH:5]=1)([OH:3])=[O:2].FC(F)(F)C(O)=O>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[O:13]=[C:11]1[C:23]2[CH:22]=[C:21]3[C:17](=[CH:16][C:15]=2[S:14][C:6]2[CH:5]=[C:4]([C:1]([OH:3])=[O:2])[CH:9]=[CH:8][C:7]=2[CH2:10]1)[CH2:18][CH2:19][CH2:20]3
Reactant: O=C(O)Cc1ccc(C(=O)O)cc1Sc1ccc2c(c1)CCC2
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc2c(c1)Sc1cc3c(cc1C(=O)C2)CCC3

Procedure:
4-Carboxy-2-(5-indanylthio)phenylacetic acid (33.55 g, 0.102 mole) was added to trifluoroacetic acid (200 ml) and to the stirred suspension was added, slowly with stirring, trifluoroacetic anhydride (200 ml). After stirring the mixture for 48 hours at room temperature, the mixture was poured slowly onto ice (200 g), and the slurry was diluted to about 1 liter before collecting the crude product. The dried solid was stirred in suspension in acetonitrile for 45 minutes, refiltered and dried to yield 24.95 g.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:19][NH:20][CH3:21].C1COCC1>CN(C=O)C.CCOC(C)=O>[CH3:19][N:20]([CH3:21])[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)nc2)c2ccccc12
Reactant: CNC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)c1ccc(-c2n[nH]c(=O)c3ccccc23)cn1

Procedure:
A mixture of the product from Example 4A (0.296 g, 1.15 mmol) and a solution of dimethylamine in THF (2 M, 2.3 mL, 4.6 mmol) in DMF (2 mL) was microwaved at 200° C. for 30 minutes, diluted with EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated to give 0.25 g of crude 4-(6-(dimethylamino)pyridin-3-yl)phthalazin-1(2H)-one, which was used without purification.
Reaction SMILES: C([NH:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[CH2:11][CH2:12][C:13]([OH:15])=O)(=O)C.P(Cl)(Cl)Cl.[P:20]([OH:23])([OH:22])[OH:21]>Cl>[NH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[CH2:11][CH2:12][C:13]([OH:15])([P:20]([OH:23])(=[O:21])[OH:22])[P:20]([OH:23])(=[O:22])[OH:21]
Reactant: CC(=O)NC1CCCCC1CCC(=O)O
Reactant: OP(O)O
Agent: Cl
Solvent: ClP(Cl)Cl
Product: N[C@H]1CCCC[C@H]1CCC(O)(P(=O)(O)O)P(=O)(O)O
Yield: 32 %

Procedure:
From the cis-trans mixture of 3-(2-acetylaminocyclohexyl)-propionic acid described in Example 10, by recrystallisation from water there is obtained the pure cis-compound (yield 32% of theory; m.p. 131°-133° C.), the reaction of which with phosphorus trichloride/phosphorous acid takes place analogously to Example 1. The course of the splitting off of the acetyl radical by heating in hydrochloric acid is monitored by means of thin layer electrophoresis.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[F:18][CH:19]([F:21])Cl>O.O1CCOCC1>[F:18][CH:19]([F:21])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1
Reactant: FC(F)Cl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccccc1)c1ccc(OC(F)F)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
100 g of 4-hydroxybenzophenone and 200 g of sodium hydroxide are dissolved in a mixture of 1 l of water and 500 ml of dioxane. The mixture is heated to 70° C. and a vigorous stream of difluorochloromethane (Frigen 22) is introduced. After 2 hours, the mixture is cooled to room temperature and 1 l of water is added to the contents of the flask. The mixture is extracted three times using 1.2 l of chloroform each time, the chloroform phase is extracted by shaking with 1N sodium hydroxide solution, washed with water and the organic phase is dried using potassium carbonate. After stripping off the solvent and subsequent distillation under vacuum, 60 g (48%) of 4-difluoromethoxybenzophenone are obtained as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)#[N:26].C(=O)([O-])[O-:37].[K+].[K+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:26][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1)=[O:37]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(Cl)nncc2c1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(-c3ccccc3C(N)=O)nncc2c1
Temperature: 120 °C

Procedure:
The title compound was prepared by a method analogous to that described in Example 11 (Method D), using a mixture of 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (0.111 g, 0.33 mmol), 2-cyanophenylboronic acid (0.211 g, 1.4 mmol), potassium carbonate (0.400 g, 2.9 mmol) and trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.017 g, 0.024 mmol) in 1.4 mL DME/0.6 mL H2O/0.4 mL EtOH, which was heated at 120° C. for 15 min. The mixture was partitioned between ethyl acetate/brine and the aqueous layer was extracted with ethyl acetate (3×). The combined organics were evaporated onto silica gel and purified using flash chromatography eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→7:93) to afford the title compound as an amorphous white solid. Found MS m/z: 423 [M+1].
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:20]=[N+:21]=[N-:22].[CH3:23][C:24]1[CH:29]=[C:28]([OH:30])[C:27]2[O:31][C:32]3[C:37]([C:38]([O:40][CH2:41][C:26]=2[CH:25]=1)=[O:39])=[C:36]([O:42][CH3:43])[C:35]([C@@H:44](O)[CH2:45][CH:46]([CH3:48])[CH3:47])=[CH:34][CH:33]=3.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1.C(Cl)Cl>[N:20]([CH:44]([C:35]1[CH:34]=[CH:33][C:32]2[O:31][C:27]3[C:28]([OH:30])=[CH:29][C:24]([CH3:23])=[CH:25][C:26]=3[CH2:41][O:40][C:38](=[O:39])[C:37]=2[C:36]=1[O:42][CH3:43])[CH2:45][CH:46]([CH3:48])[CH3:47])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=N
Reactant: COc1c([C@@H](O)CC(C)C)ccc2c1C(=O)OCc1cc(C)cc(O)c1O2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1c(C(CC(C)C)N=[N+]=[N-])ccc2c1C(=O)OCc1cc(C)cc(O)c1O2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4.6 g (17.6 mmol) of triphenylphosphine and 29.3 ml of a freshly prepared 0.6 N solution of hydrazoic acid in toluene are added to 6 g (16.1 mmol) of penicillide (1b) in 100 ml of tetrahydrofuran. 2.7 ml (17.6 mmol) of diethyl azodicarboxylate are added dropwise to this mixture at 0° C. under argon. The mixture is then stirred at 25° C. for 12 h. After diluting with methylene chloride, the mixture is washed with aqueous bicarbonate, dried and evaporated. Chromatography on silica gel Si60 in diethyl ether/petroleum ether =2:1 yields 5.6 g (88% of theory) of colorless solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.C(N(C(C)C)CC)(C)C.[C:28]1([C:34]#[CH:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(#N)C>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[N:4]1[C:5]2[C:10](=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=2)[C:2]([C:35]#[C:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:3]1
Reactant: C#Cc1ccccc1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1ccc2c(c1)c(C#Cc1ccccc1)nn2C1CCCCO1
Yield: 76.2 %

Procedure:
A mixture of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (400 mg, 1.31 mmol), 10.0 mL of acetonitrile (CH3CN), diisopropylethylamine (172 mg, 1.33 mmol, 1.01 equiv.), dichlorobis(triphenylphosphine)palladium(II) [(Ph3)P2PdCl2, 0.0187 mmol, 0.0143 equiv.), copper (I) iodide (CuI, 13.1 mg, 0.0688 mmol, 0.0525 equiv.), and phenylacetylene (147 mg, 1.44 mmol, 1.10 equiv.) were refluxed for 3 h and concentrated. Purification by silica gel chromatography using 20–30% EtOAc in hexanes afforded the title compound (327 mg, 76.2% yield): ES-MS (m/z) 328 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:19]=[C:12]2[CH:13]=[N+:14]([O-])[CH:15]=[C:16]([F:17])[C:11]2=[N:10]1.P(Br)(Br)([Br:22])=O>ClCCCl>[Br:22][C:13]1[C:12]2=[CH:19][N:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[N:10]=[C:11]2[C:16]([F:17])=[CH:15][N:14]=1
Reactant: [O-][n+]1cc(F)c2nn(-c3c(Cl)cccc3Cl)cc2c1
Reactant: O=P(Br)(Br)Br
Solvent: ClCCCl
Product: Fc1cnc(Br)c2cn(-c3c(Cl)cccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
To a cooled (0° C.) solution of 2-(2,6-dichlorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine 5-oxide (2.5 g, 8.4 mmol) in DCE (55 mL) under nitrogen was added phosphorous oxybromide (7.2 g, 25.2 mmol). The reaction mixture was stirred for 30 minutes, warmed to room temperature, and stirred for a further 4 hours. The reaction was quenched with sodium carbonate (sat. aq.) and the layers were partitioned. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography (20% ethyl acetate in cyclohexane) to afford the title compound as a white solid (927 mg, 31% yield). LCMS (Method D): RT=3.74 min, m/z: 360 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[S:11][CH2:12][CH2:13][CH3:14].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]=[C:22]=[O:23])[CH:16]=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:22](=[O:23])[NH:21][C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)=[CH:4][C:3]=1[S:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C=Nc1cccnc1
Reactant: CCCSc1cc2c(cc1Br)NCC2
Product: CCCSc1cc2c(cc1Br)N(C(=O)Nc1cccnc1)CC2
Yield: 65 %

Procedure:
6-Bromo-5-propylthioindoline (D83) (0.095 g, 0.35 mmol) was treated with 3-pyridylisocyanate as in the procedure described in Example 1. The product was recrystallised from ethanol/diethyl ether to give the title compound (0.089 g, 65%) as a white crystalline solid m.p. 224°-226° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:7]=1.I[CH2:27][CH:28]1[CH2:30][CH2:29]1>>[Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH:8]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:7]=1
Reactant: CC(C)(C)OC(=O)Cn1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: ICC1CC1
Product: CC(C)(C)OC(=O)C(CC1CC1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
349 mg (0.91 mmol) of tert-butyl [5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate and 216 mg (1.18 mmol) of (iodomethyl)cyclopropane were reacted according to General Method 7A. Yield: 245 mg (62% of theory)
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[C:13](=[C:15]([O:22][CH3:23])[CH:16]=[CH:17][C:18]=3[C:19]([OH:21])=[O:20])[O:14][C:8]=2[CH2:7]1)=[O:5])[CH3:2].[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].CCN=C=NCCCN(C)C.Cl.O>CN(C1C=CN=CC=1)C.O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[C:13](=[C:15]([O:22][CH3:23])[CH:16]=[CH:17][C:18]=3[C:19]([O:21][C:30]3[CH:31]=[CH:32][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][CH:29]=3)=[O:20])[O:14][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C(=O)O)c23)C1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C(=O)Oc4ccc([N+](=O)[O-])cc4)c23)C1

Procedure:
A solution of 2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine-5-carboxylic acid (from step 7) (0.352 g, 1.1 mmol), 4-nitrophenol (0.229 g, 1.65 mmol), EDCl (0.253 g, 1.32 mmol) and 4-(N,N-dimethyl)aminopyridine (0.027 g, 0.22 mmol) in tetrahydrofuran was stirred overnight. Water was added to RM, extracted with ethyl acetate and org layer was concentrated after drying on anhy. Sod. Sulphate. The solid was chromatographed on silica gel to yield 4-nitrophenyl 2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine-5-carboxylate.
Reaction SMILES: [C:1](=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]1[C:16]([S:17]([OH:19])=[O:18])=[CH:15][CH:14]=[C:13]([F:20])[C:9]=1[C:10]([OH:12])=[O:11].CI>CO.O>[F:7][C:8]1[C:16]([S:17]([CH3:1])(=[O:19])=[O:18])=[CH:15][CH:14]=[C:13]([F:20])[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1c(F)ccc(S(=O)O)c1F
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CI
Product: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 18 mmol sodium carbonate and 9 mmol 2,6-Difluoro-3-sulfino-benzoic acid in 30 ml of methanol was stirred at room temperature for 30 min, then heated to 60° C. 24 mmol of methyl iodide were added and the reaction mixture heated overnight at 60° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was discarded and the aqueous phase acidified by addition of concentrated hydrochloric acid. Extraction with ethyl acetate yielded the title compound as a slightly brownish solid. MS (m/e): 235.1 (M−H, 16%)
Reaction SMILES: I.I.[N:3]1([C:10]2[N:14]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[N:11]=2)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[CH:28][C:27]=1[C:37]([N:39]1[CH2:43][CH2:42][C@:41]([CH2:50][CH2:51]OS(C)(=O)=O)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:38].C(N(CC)CC)C>C(#N)C>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[CH:28][C:27]=1[C:37]([N:39]1[CH2:43][CH2:42][C@@:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([CH2:50][CH2:51][N:6]2[CH2:7][CH2:8][CH2:9][N:3]([C:10]3[N:14]([CH2:15][C:16]([F:19])([F:17])[F:18])[C:13]4[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=4[N:11]=3)[CH2:4][CH2:5]2)[CH2:40]1)=[O:38]
Reactant: FC(F)(F)Cn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccccc2)C1
Agent: I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCN2CCCN(c3nc4ccccc4n3CC(F)(F)F)CC2)(c2ccccc2)C1
Yield: 77 %

Procedure:
Reflux a stirred solution of 2-[1,4]diazepan-1-yl-1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole dihydroiodide (0.44 g, 0.79 mmol), methanesulfonic acid 2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethyl ester (0.38 g, 0.79 mmol, example 47.2), triethylamine (2.54 mmol) and acetonitrile (11 mL) under argon for 20 hours. Cool and concentrate in vacuo. Dilute with dichloromethane (100 mL), wash the organic phase with NaHCO3 solution (2×20 mL), dry (Na2SO4) the organic phase, filter and evaporate in vacuo. Purify the residue by flash chromatography (silica gel, 7×15 cm) eluting with 10% methanol/0.1% ammonium hydroxide solution in dichloromethane, concentrate the appropriate fractions, and dry the resultant material in vacuo (0.2 Torr) for 2 hours to afford 0.41 g of the title compound as a beige colored foam, Rf=0.39 (silica gel, 10% methanol/0.1% ammonium hydroxide solution in dichloromethane). The compound may be converted to the dihydrochloride salt by methods well known in the art.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:8]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:6][N:5]2[CH:15]=1.CN(C)[C:18]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[O:19]>>[CH:12]([O:11][C:9]([CH:8]1[CH2:7][CH2:6][N:5]2[C:15]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[O:19])=[C:2]([CH3:1])[CH:3]=[C:4]12)=[O:10])([CH3:13])[CH3:14]
Reactant: Cc1ccc(C(=O)N(C)C)cc1
Reactant: Cc1cc2n(c1)CCC2C(=O)OC(C)C
Product: Cc1ccc(C(=O)c2c(C)cc3n2CCC3C(=O)OC(C)C)cc1

Procedure:
In accordance with the method of Example 8, isopropyl 1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate is condensed with N,N-dimethyl-p-toluamide, to produce isopropyl-5-p-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (XI, R = CH3, R1 = p-CH3, R2 = iC3H7).
Reaction SMILES: [CH2:1]([CH2:11]/[C:12](/[CH3:25])=[CH:13]/[CH2:14][CH2:15]/[C:16](/[CH3:24])=[CH:17]/[CH2:18][CH2:19][C:20]([O:22]C)=O)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:20](=[O:22])[CH2:19][CH2:18]/[CH:17]=[C:16](/[CH2:15][CH2:14]/[CH:13]=[C:12](\[CH3:25])/[CH2:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])\[CH3:24])[CH2:29][CH2:28]1
Reactant: CN1CCNCC1
Reactant: COC(=O)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CCC(=O)N1CCN(C)CC1
Yield: 51.2 %

Procedure:
A three-necked flask equipped with a thermometer and a stirrer was charged with 69.2 g of methyl geranylgeranylacetate and 17.0 g of N-methylpiperazine. They were heated at 150° to 200° C. in an atmosphere of nitrogen for 3 hours with stirring. After cooling, the reaction mixture was chromatographed on a column of 3 kg of silica gel using a mixture of chloroform and methanol (7:1 by volume) as an eluent, and then further chromatographed on a column of 1.5 kg of silica gel using a mixture of ethyl acetate, ethanol and benzene (1:1:1 by volume) as an eluent to give 36 g of pure N-methyl-N'-geranylgeranylacetyl piperazine [compound (2)] as an oil. The structure of the product was determined from the following analytical results.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][OH:11])[O:8][C@@H:7]([N:12]2[CH:19]=[C:18](I)[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)[CH:2]=[CH2:3].C(N(CC)CC)C.[CH2:28]([NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[C:29]#[CH:30]>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][OH:11])[O:8][C@@H:7]([N:12]2[CH:19]=[C:18]([C:30]#[C:29][CH2:28][NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C#CCNC(=O)C(F)(F)F
Reactant: C=CCO[C@H]1C[C@H](n2cc(I)c(=O)[nH]c2=O)O[C@@H]1CO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCO[C@H]1C[C@H](n2cc(C#CCNC(=O)C(F)(F)F)c(=O)[nH]c2=O)O[C@@H]1CO
Reaction time: 16 h
Yield: 95.4 %

Procedure:
To a solution of (35) (400 mg, 1.0 mmol) in dry DMF (10 ml) was added CuI (38 mg, 20 μmol) and triethylamine (300 μl, 2.0 mmol). The propargyltrifluoroacetamide (453 mg, 3.0 mmol) was added drop wise, followed by Pd(PPh3)4 (110 mg, 9.5 μmol). The reaction was stirred for 16 h in the dark. The reaction was quenched by adding MeOH (10 ml), DCM (10 ml) and bicarbonate dowex. The mixture was stirred for 30 min and then filtered. The solvents were removed under vacuum and the crude product was purified by chromatography on silica (EtOAc:petrol 3:7 to 7:3). The product was isolated as slightly yellow crystals (398 mg, 95%). 1H NMR (d6 DMSO) δ 2.25-2.43 (m, 2H, H-2′), 3.65-3.76 (m, 2H, H-5′), 4.07-4.17 (m, 3H, H-4′, CH2), 4.21-4.23 (m, 1H, H-3′), 4.34 (d, J=5.5 Hz, 2H, CH2N), 5.25-5.27 (m, 2H, ═CH2, OH), 5.38 (dd, J=1.83, 17.3 Hz, 1H, ═CH2), 5.96-6.06 (m, 1H, ═CH), 6.17 (t, J=6.9 Hz, 1H, H-1′), 8.29 (8, 1H, H-6), 10.17 (t, J=5.5 Hz, 1H, NHTFA), 11.78 (s, 1H, NH). Mass (−ve electrospray) calcd for C17H18F3N3O6 417.11, found 416.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C@@H:8]([NH:12][C:13](=O)[C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[OH:15])[CH2:9]2)=[CH:4][CH:3]=1.B.CSC.B#B.B.CSC>O1CCCC1.CO>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C@@H:8]([NH:12][CH2:13][C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[OH:15])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1CCc2ccc(O)cc2C1)[C@@H](O)c1cccc(Cl)c1
Agent: B
Agent: B#B
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: Oc1ccc2c(c1)C[C@H](NC[C@@H](O)c1cccc(Cl)c1)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3 g of N-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(S)-3-chloromandelamide, SR 58588, PREPARATION VI, in 40 ml of anhydrous tetrahydrofuran, heated with reflux under nitrogen stream, there is added 2.7 ml of a 10M solution of borane-methylsulfide (reagent which generates diborane consisting of a complex of borane and dimethylsulfide) in 20 ml of tetrahydrofuran, and heated for 4 hours with reflux. To the solution cooled at room temperature, there is added 25 ml of methanol and the reaction mixture is left under stirring at first 30 minutes at room temperature, then, 30 minutes with reflux. After concentration under reduced pressure and filtration, the residue is crystallized twice from isopropanol to give the N-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(2S)-2-(3-chlorophenyl)-2-hydroxyethanamine, SR 58590; m.p. 186°-188° C.; |alpha|=+76° (methanol, c=0.5%).