Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]([C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[N:7]2[C:25](=[O:36])[C@@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C@H:6]2[S:5][CH:4]=1)=O.[CH3:37][C:38]([CH:40]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:39]>C1C=CC=CC=1>[CH3:37][C:38](/[CH:40]=[CH:1]/[C:3]1[CH:8]([C:9]([O:11][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:10])[N:7]2[C:25](=[O:36])[C@@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C@H:6]2[S:5][CH:4]=1)=[O:39]
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1=CS[C@@H]2[C@H](NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CC(=O)/C=C/C1=CS[C@@H]2[C@H](NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Yield: 25.6 %

Procedure:
A solution of diphenylmethyl 3-formyl-7β-(2-thienylacetamido)ceph-2-em-4-carboxylate (116 mg.) in benzene (3 ml.) was treated with a solution of methylcarbonylmethylenetriphenylphosphorane (150 mg.) in benzene (4 ml.) and the mixture refluxed for 5.75 hours. The organic solution was washed with 2-N-hydrochloric acid and water, dried and evaporated in vacuo. The residual gum (186 mg.) was purified by preparative T.L.C. (Kieselgel HF254+366, developed five times with benzene-ethyl acetate = 8:1) to give the title compound (32 mg, 27%) as a gum, λmax. (CHCl3) 318 nm. (qualitative, τ (CDCl3) 3.00 and 3.86 (CH=CH, two d, J 16 Hz), 3.12 (CHPh2), 3.27 (C(2) -H, broad s), 4.47 (C(7) -H), dd, J 8 and 4 Hz), 4.73 (C(6) -H, d, J 4 Hz), 4.69 (C(4) -H, broad s), 6.16 (CH 2 CONH) and 7.91 (COCH3).
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=O)[CH2:4][CH2:3]1.[CH3:8][CH:9]([SH:11])[CH3:10]>CCOCC>[CH:9]([S:11][CH:5]1[NH:6][C:2](=[O:1])[CH2:3][CH2:4]1)([CH3:10])[CH3:8]
Reactant: O=C1CCC(O)N1
Reactant: CC(C)S
Solvent: CCOCC
Product: CC(C)SC1CCC(=O)N1
Temperature: 25 °C

Procedure:
A mixture of 9 g of 5-hydroxy-pyrrolidin-2-one in 40 cm3 of 2-propanethiol and 5 g of Amberlite resin IR 120 H is maintained for 80 hours at ambient temperature. After diluting with ether, filtering, and concentrating under reduced pressure, 8.5 g of the expected product is obtained. m.p. 77°-79° C., crystallized from isopropyl ether. m.p. 85°-87° C. after re-crystallization.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:9]([CH2:13][O:14][CH:15]([F:17])[F:16])[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.Cl.[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1.C(OCC)(=O)C>[CH2:18]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]([CH2:13][O:14][CH:15]([F:16])[F:17])[C:10]([NH:48][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:12])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)C(COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)C(COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.5 %

Procedure:
To a solution of 2-(dibenzylamino)-3-(difluoromethoxy)propanoic acid (335.4 mg, 1 mmol) and triethylamine (404.8 mg, 4 mmol) in THF (5 mL) at −5° C., isobutyl chloroformate (143.5 mg, 1.05 mmol) was added dropwise. After 20 minutes, benzylamine hydrochloride (215.4 mg, 1.5 mmol) was added and the reaction mixture was allowed to warm up to room temperature. The mixture was then diluted with ethyl acetate and washed with water, 0.5N HCl and Brine. The organic layer was dried over magnesium sulphate, concentrated with silica gel and purified by column chromatography, eluting with 10-20% ethyl acetate in hexanes to give 2-(dibenzylamino)-3-(difluoromethoxy)-N-benzylpropanamide (367 mg, 86.5%) as a white solid. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.56 (t, 1H), 7.17-7.34 (m, 15H), 6.35 (wt, 1H), 4.60 (dd, 1H), 4.43 (m, 3H), 3.95 (d, 2H), 3.68 (d, 2H) and 3.67 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]2[C:9](=[S:13])[NH:10][N:11]=[CH:12][C:7]2=[CH:6][N:5]=1.[H-].[Na+].I[CH3:17]>CN(C)C=O>[CH3:1][O:2][CH2:3][C:4]1[N:8]2[C:9]([S:13][CH3:17])=[N:10][N:11]=[CH:12][C:7]2=[CH:6][N:5]=1
Reactant: COCc1ncc2cn[nH]c(=S)n12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1ncc2cnnc(SC)n12

Procedure:
A slurry of 0.98 gm of 6-(methoxymethyl)-imidazo[1,5-d]-as-triazine-4(3H)-thione in 10 ml of N,N-dimethylformamide is treated with 0.28 gm of 50% sodium hydride in oil. Gentle warming is applied until the effervescence stops and then 0.41 ml of iodomethane is added. The resulting precipitate is collected, washed with ether, recrystallized from acetone then ethanol, to yield the above-noted desired product having a melting point equal to 179°-181° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[C:18]([NH:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[O:2][CH3:1])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccccc1CN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1CNC(=O)c1ccccc1
Temperature: 16 °C
Yield: 87.1 %

Procedure:
To a mixture of o-methoxybenzylamine (20.0 g, 0.146 mol), tetrahydrofuran (124 mL) and triethylamine (15.6 g, 0.154 mol) was added dropwise benzoyl chloride (20.5 g, 0.146 mol) at −9-0° C., and the dropping funnel was washed with THF (10 mL). Under a nitrogen atmosphere, the reaction mixture was gradually warmed to about 16° C. During warming, THF (total 51 ml) was appropriately added to stir the content. The reaction was confirmed by TLC (eluent: hexane/ethyl acetate (1:1)). The reaction mixture was stirred at about 16° C. for 10 hr, and cooled to 5° C. Water (44 ml) was added thereto, and the mixture was extracted three times with ethyl acetate (120 mL, 40 mL, 40 mL). The combined organic layers were washed successively with 10% hydrochloric acid (40 mL), saturated aqueous sodium hydrogen carbonate solution (40 mL), water (40 mL) and saturated brine (44 mL), and dried over magnesium sulfate (20 g), and the solvent was evaporated under reduced pressure at 40° C. or lower. Ethyl acetate was added to the residue (content 74 g), and the solid was dissolved with heating to 60° C. The solution was gradually cooled to 6° C., the precipitated crystals were collected by filtration, washed with cold ethyl acetate (10 mL), and dried under reduced pressure at 40° C. or lower to give N-benzoyl-2-methoxybenzylamine (30.7 g, 87.1%) as white crystals.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([OH:14])[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22]([O:25][CH:26]=[CH2:27])(=[O:24])[CH3:23].C(Cl)(Cl)Cl>COC(C)(C)C>[CH2:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([OH:14])[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([O:8][C@@H:9]1[CH2:13][C@H:26]([O:25][C:22](=[O:24])[CH3:23])[CH:27]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=COC(C)=O
Agent: O[C@@H]1C=C[C@H](OCc2ccccc2)C1
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@@H]1C=C[C@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 70 %

Procedure:
Cis-4-benzyloxy-cyclopent-2-enol (500 mg, prepared in example 16) is dissolved in tert-butyl methyl ether (8.6 mL, anhydrous). To the solution is added triethylamine (0.7 eq), pancreatin (3 wt eq, available from Sigma Chemical Company), and vinyl acetate (5 eq). The reaction is allowed to stir for 7 hours at room temperature. The reaction is then filtered through diatomaceous earth and the filtrate is concentrated under vacuum. The products are separated by chromatography on silica gel (20% ethyl acetate/hexane) to provide (-)-cis-4-benzyloxy-cyclopent-2-enol (A) (147 mg, 29% yield) [α]20D --12°, (c=1.09, chloroform), and (-)-acetic acid cis-4-benzyloxy-cyclopent-2-enyl ester (B) (427 mg, 70% yield),[α]20D =-5.2°, (c=0.97, chloroform), 1 H NMR (CDCl3) δ 7.3 (m, 5 H), 6.13 (d, 1 H, J=5 Hz), 5.99 (d, 1 H, J=5 Hz), 5.5 (m, 1 H), 4.59 (d, 1 H, J=11.8 Hz), 4.54 (d, 1 H, J=11.8 Hz), 4.5 (m, 1 H), 2.78 (d appt, 1 H, J=7.2, 14.3 Hz), 2.05 (s, 3 H) , 1.76 (d appt, 1 H, J=4.4, 14.3 Hz); 13C NMR (CDCl3) δ 171.1, 138.5, 136.4, 133.1, 128.7, 128, 127.9, 81.4, 77.1, 71.2, 37.8, 21.4.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]([NH:22][NH2:23])=[O:21])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[C:24]([N:27]=[C:28]=[S:29])(=[O:26])[CH3:25]>ClCCCl>[NH2:1][C:2]1[C:3]([C:20]([NH:22][NH:23][C:28]([NH:27][C:24](=[O:26])[CH3:25])=[S:29])=[O:21])=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:15])=[O:16])=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: CC(=O)N=C=S
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)NN)n2)cc1
Solvent: ClCCCl
Product: CC(=O)NC(=S)NNC(=O)c1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-amino-6-(4-isopropylsulfonylphenyl)pyrazine-2-carbohydrazide (100 mg, 0.2982 mmol), acetyl isothiocyanate (30.16 mg, 26.20 μL, 0.2982 mmol) and dry DCE (2.000 mL) were stirred at ambient temperature for 2 h and then concentrated in vacuo. Used directly in the next step without further purification; MS (ES+) 437.20
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([OH:15])=[O:14])[CH2:5]1)#[N:2].[C:16](O)([CH3:19])([CH3:18])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1)#[N:2]
Reactant: CC1(C)O[C@H](CC#N)C[C@H](CC(=O)O)O1
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC(C)(C)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-cis-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid (3.72 g, 17.44 mmol) is dissolved in 20 mL of dichloromethane, cooled to 0° C. and 0.2 g of 4-dimethylaminopyridine (DMAP) is added, followed by t-butyl alcohol and followed by 4.32 g of dicyclohexylcarbodiimide (DCC). This solution is allowed to slowly warm to room temperature over a 76.5-hour period. Thin layer chromotography (TLC) shows mainly product, and some slightly lower Rf by-products. The mixture is stirred one hour and 50 mL of dichloromethane is added and stirring continues five hours. An additional 100 mL of diethyl ether is added and the mixture filtered. The precipitate is washed with diethyl ether. The filtrate is concentrated to an oil. The crude product is chromatographed on silica gel eluting with 4:1 hexane:ethyl acetate. The eluate is concentrated to yield (±)-cis-1,1-dimethylethyl 6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([S:16](Cl)(=[O:18])=[O:17])[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[Cl:7].[CH3:20][NH:21][CH3:22]>CC(C)=O.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([S:16]([N:21]([CH3:22])[CH3:20])(=[O:18])=[O:17])[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[Cl:7]
Reactant: C[Si](C)(C)CCOCn1c(S(=O)(=O)Cl)nc(Cl)c1Cl
Reactant: CNC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CN(C)S(=O)(=O)c1nc(Cl)c(Cl)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution of 4,5-dichloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-sulfonyl chloride (0.826 mmol) in acetone (2.5 mL) and THF (1.5 mL) was added to dimethylamine (2.0 mL of a 2M solution in THF, 4.0 mmol). The reaction mixture was stirred at RT for 1 h and then evaporated to dryness. The residue was taken up in EtOAc and washed with brine. The organic layer was dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (0-30% EtOAc/hexanes) to provide the title compound (0.18 g, 57%) as a light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.62 (s, 2H), 3.61-3.75 (m, 2H), 3.06 (s, 6H), 0.84-1.00 (m, 3H), 0.00 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9]Cl>CN(C)C=O>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: ClCl
Reactant: Oc1cccnc1Cl
Solvent: CN(C)C=O
Product: Oc1ccc(Cl)nc1Cl
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
100 g (0.77 mole) of 2-chloro-3-pyridinol (I) was dissolved in 350 ml of dimethylformamide. 70 ml of chlorine (measured at -80°; 0.93 mole) was introduced in the course of 1.5 hours into the stirred solution at 0°. The reaction mixture was then stirred for 1.5 hours at 20° C. and subsequently concentrated in a rotary evaporator (bath: 50°; 10 torr). 400 ml of water and 100 ml of ether were added to the residue; the two phases were separated and the aqueous phase was extracted 5 times with 100 ml of ether each time. The combined ether phases were washed with water and dried. The solvent was removed in vacuo; the semisolid residue was stirred with 1.6 liters of water, and the resulting suspension was adjusted to pH 3. The suspension was heated to boiling, and after a few minutes the solution was decanted from an oily residue. The solution was purified with active charcoal, and the yellow product obtained on cooling was recrystallised from water; m.p. 136°-138° C.; yield 42 g.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:22])[C@@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[CH:7]=1.C1COCC1.[BH4-].[Na+]>C(O)C>[Cl:1][CH2:2][C@@H:3]([OH:22])[C@@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:5][C:6]1[CH:7]=[C:8]([F:13])[CH:9]=[C:10]([F:12])[CH:11]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CCl
Reaction time: 2 h

Procedure:
To a 250 mL 3-neck round bottom flask equipped with magnetic stir bar, nitrogen inlet and thermocouple, is added tert-butyl (1S)-3-chloro-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate (III, EXAMPLE 2, 4.4 g, 0.0132 moles, 1 equivalent) followed by THF (20 mL) and ethanol (30 mL) then cooled to −78°. Once the mixture is cooled, sodium borohydride (2.0 g, 0.0527 moles, 4 equivalents) is added as a solid portion wise over 30 min keeping the internal temperature below −70°. Once this addition is complete, the contents are stirred for 2 hr at −78° then warmed to 0° and stirred an additional 1 hr. The mixture is quenched by the addition of saturated potassium bisulfate (15 mL) and water (15 mL). This slurry is stirred for 30 min at 20-250 then concentrated under reduced pressure to half its volume. The mixture is then cooled to 0° and stirred for 30 min. After this time, the resultant solids are collected by filtration and washed with water (2×50 mL) then dried under reduced pressure at 50° to give crude product. A syn/anti ratio of 4-9:1 has been observed. The desired product is recrystallized from hexanes/ethanol (25/1) to give the title compound, mp=149°; NMR (DMSO-d6) δ 6.89-7.16, 5.61, 3.64-3.83, 3.19, 2.69 and 1.41; CMR (DMSO-d6) δ 163.67, 161.24, 155.44, 112.70, 101.55, 78.04, 72.99, 54.29, 48.24, 35.97 and 28.37.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20](Cl)=[N:21][CH:22]=[N:23]2)=[CH:18][C:17]=1[O:27][CH3:28])[CH2:12][CH2:13][CH3:14]>CC(O)C>[CH2:11]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([N:8]3[C:9]4[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=4)[CH2:6][CH2:7]3)=[N:21][CH:22]=[N:23]2)=[CH:18][C:17]=1[O:27][CH3:28])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: Clc1ccc2c(c1)NCC2
Solvent: CC(C)O
Product: CCCCOc1cc2ncnc(N3CCc4ccc(Cl)cc43)c2cc1OC
Yield: 43 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 43% yield from 6-chloro-indoline (1.1 eq.) and 7-butoxy-4-chloro-6-methoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 126°-132° C.; GC-MS: 383 (M+); anal. RP18-HPLC RT: 6.22 min.).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=[CH:9][C:8]([Cl:19])=[CH:7][CH:6]=2.[C:20](#[N:23])[CH:21]=[CH2:22]>>[ClH:19].[Cl:19][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3]([CH2:2][NH:1][CH2:22][CH2:21][C:20]#[N:23])=[C:11]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18]
Reactant: NCc1[nH]c2ccc(Cl)cc2c1-c1ccccc1F
Reactant: C=CC#N
Product: Cl
Product: N#CCCNCc1[nH]c2ccc(Cl)cc2c1-c1ccccc1F

Procedure:
Treat 1.3 g of 2-aminomethyl-5-chloro-3-(2-fluorophenyl)indole with 8 ml of acrylonitrile and reflux for 16 hours. Concentrate to a residue and dissolve the residue in alcohol, e.g. ethanol. Add an ethanolic solution of hydrogen chloride, collect and dry the solid which precipitates out; the title compound melts at 212- 213°C.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][C:7]1[CH:18]=[CH:17][CH2:16][C:15]2[C:8]=1[CH:9]=[C:10]1[C:14]=2[CH:13]=[N:12][N:11]1[CH2:19][CH:20](O)[CH3:21].C(N(CC)CC)C.[N-:30]=[N+:31]=[N-:32].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:30]([CH:20]([CH3:21])[CH2:19][N:11]1[C:10]2=[CH:9][C:8]3[C:15]([CH2:16][CH:17]=[CH:18][C:7]=3[CH3:6])=[C:14]2[CH:13]=[N:12]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1=C2C=c3c(cnn3CC(C)O)=C2CC=C1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1=C2C=c3c(cnn3CC(C)N=[N+]=[N-])=C2CC=C1
Yield: 73.1 %

Procedure:
1.15 ml (14.8 mmol) of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 1.7 g (7.45 mmol) of (RS)-1-(7-methyl-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-propan-2-ol and 4.12 ml (29.7 mmol) of triethylamine in 60 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 50 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 50 ml of dichloromethane. The combined organic phases were washed with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellow oil obtained was dissolved in 40 ml of anhydrous dimethylformamide, treated with 0.96 g (14.8 mmol) of sodium azide and the reaction mixture was heated to 70° for 15 hours while stirring. After cooling, the solution was poured into 100 ml of semi-saturated sodium chloride solution and extracted twice with 100 ml of diethyl ether each time. The combined organic phases were washed once with 80 ml of water and once with 80 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.38 g (73%) of (RS)-1-(2-azido-propyl)-7-methyl-1,4-dihydro-indeno[2,1-c]pyrazole were obtained as a light yellow solid with m.p. 70°-72°.
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][CH:10]=[C:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[CH2:25](O)[CH2:26][OH:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:25]1[CH2:26][O:27][C:12]([C:11]2[C@:15]3([CH3:24])[C@H:8]([C@H:7]4[C@H:18]([C:17](=[O:23])[CH2:16]3)[C@:19]3([CH3:22])[C@H:4]([CH2:3][C@@H:2]([OH:1])[CH2:21][CH2:20]3)[CH2:5][CH2:6]4)[CH2:9][CH:10]=2)([CH3:13])[O:14]1
Reactant: OCCO
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C2=CC[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1
Reaction time: 20 h

Procedure:
3β-Hydroxy-5α-pregn-16-ene-11,20-dione (3 g) was refluxed with ethylene glycol (8 ml) in benzene (150 ml) containing p-toluenesulphonic acid (150 mg) under a Dean Stark water separator for 20 hours. The mixture was diluted with ethyl acetate, washed with sodium hydrogen carbonate solution, and brine, and dried (sodium sulphate). Evaporation gave 20,20-ethylenedioxy-3β-hydroxy-5α-pregn-16-en-11-one (3.42 g) as a white foam. This foam was dissolved in ethanol (170 ml) and sodium borohydride (2.1 g) in water (21 ml) was added with stirring under reflux. After 1.25 hours, most of the ethanol was evaporated and the residue was partitioned between ethyl acetate and water. The ethyl acetate extract was washed, and evaporated to small volume. This solution was filtered through silica gel (100 g) in ethyl acetate. Evaporation of the eluate gave 20,20-ethylenedioxy-5α-pregn-16-ene-3β,11β-diol (2.45 g) as a white foam which was heated on a steam bath for 1 hour in acetic acid (24 ml) and water (25 ml). The mixture was concentrated and diluted with water. The solid was collected by filtration, washed, and dried. Recrystallisation from ethyl acetate-acetone gave title compound (97 mg), m.p. 214°-218°, [α]D +82.1°.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][CH2:12][N:13]([CH3:33])[C:14]1[C:22]2[O:21][CH:20]=[CH:19][C:18]=2[CH:17]=[C:16]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:15]=1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:42]>>[ClH:42].[CH3:33][N:13]([CH2:12][CH2:11][CH2:10][NH:2][CH3:1])[C:14]1[C:22]2[O:21][CH:20]=[CH:19][C:18]=2[CH:17]=[C:16]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:15]=1
Reactant: CN(CCCN(C)c1cc(NS(=O)(=O)c2ccccc2)cc2ccoc12)C(=O)OC(C)(C)C
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCCN(C)c1cc(NS(=O)(=O)c2ccccc2)cc2ccoc12
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
tert-Butyl methyl[3-(methyl{5-[(phenylsulfonyl)amino]-1-benzofuran-7-yl}amino)propyl]carbamate (Intermediate 3; 202 mg, 0.43 mmol) in DCM (2 mL) was treated with TFA (2 mL) at 0° C. for 10 min and was stirred for an additional 30 min at room temperature. After concentration in vacuo, the residue was re-dissolved in MeOH and treated with an excess of 1M HCl in diethyl ether. Removal of the solvents gave the title compound (173 mg, 98%) as a white solid; HPLC 100%, RT: 1.65 min (System A); 100%, RT: 0.630 min (System B); 1H NMR (methanol-d4) δ ppm 1.85-2.00 (m, 2H), 2.67 (s, 3H), 3.04-3.17 (m, 5H), 3.64-3.73 (m, 2H), 6.81-6.84 (m, 1H), 6.95-6.98 (m, 1H), 7.06-7.09 (m, 1H), 7.43-7.60 (m, 3H), 7.72-7.78 (m, 2H), 7.81-7.85 (m, 1H); MS m/z 374 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:23][C:24](=[O:40])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([N:34]5[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]5)[CH:29]=4)[CH2:25][C:24](=[O:40])[NH:23][C:9]=3[CH:10]=2)=[CH:21][CH:20]=1
Reactant: Cc1cn(-c2cccc(C(=O)CC(=O)Nc3cc(C#Cc4ccc(F)cc4)ccc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cn(-c2cccc(C3=Nc4ccc(C#Cc5ccc(F)cc5)cc4NC(=O)C3)c2)cn1

Procedure:
Prepared from (4-(4-fluoro-phenylethynyl)-2-{3-[3-(4-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert.-butyl ester (Example K49) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (122 mg).