Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:5]C=C[CH2:2]1.C[N+]1([O-])CCOCC1.[O:26]1[CH2:31][CH2:30][O:29]CC1.O>O=[Os](=O)(=O)=O>[OH:26][C@H:31]1[C@@H:30]([OH:29])[CH2:2][CH:1]([O:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:5]1
Reactant: C1COCCO1
Reactant: O=C1c2ccccc2C(=O)N1OC1CC=CC1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OC1C[C@@H](O)[C@@H](O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
To a solution of 2-(cyclopent-3-enyloxy)isoindoline-1,3-dione (736 mg, 3.2 mmol) in dioxane —H2O (5.0 mL, 4:1) was added NMO (421 mg, 3.60 mmol) and OsO4 (1.0 mL mg, 0.32 mmol, 2.5 wt % in H2O) and the reaction mixture was stirred for 24 h at rt. Quenched with 10% aqueous Na2S2O3 solution and extracted with ethyl acetate. The combined organic layers washed with brine and dried over anhydrous Na2SO4. Filtered and concentrated to provide yellow oil, which was purified by flash chromatography (80% EtOAc-hexane) to yield 2-((3R,45)-3,4-dihydroxycyclopentyloxy)isoindoline-1,3-dione (650 mg, 77%) as light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.94-2.12 (m, 2H) 2.14-2.35 (m, 2H) 4.22-4.88 (m, 2H) 4.75-5.11 (m, 1H) 7.67-7.78 (m, 2H) 7.79-7.86 (m, 2H). MS (ES) [M+H] calculated for C13H14NO5, 264.08; found 264.20.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[NH:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH:26]([CH3:28])[CH3:27]>CN(C=O)C>[CH2:25]([N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)CBr
Reactant: c1ccc(CCc2nc3ccccc3[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CCc2ccccc2)nc2ccccc21
Temperature: 90 °C
Yield: 63.9 %

Procedure:
A 100 mL flask fitted with a stir-bar and septum with an Ar inlet was charged with benzimidazole 67 (2.00 g, 9.00 mmol) and K2CO3 (2.49 g, 18.0 mmol). DMF (25 mL) was added followed by 1-bromo-2-methylpropane (1.84 g, 1.47 mL, 13.5 mmol), and the mixture was heated in a 90° C. bath overnight. Another 1 mL of 1-bromo-2-methylpropane was added and the mixture was heated overnight again. Another addition of 1 mL of 1-bromo-2-methylpropane and 1 g K2CO3 was executed, and the mixture was heated overnight again. The suspension was cooled, and the solids were filtered off and rinsed with EtOAc (80 mL). The filtrate was washed with saturated NH4Cl (2×50 mL), H2O (2×50 mL), and brine (30 mL), filtered through phase separation paper, and concentrated in vacuo to an orange oil. The crude oil was filtered through a plug of silica gel with CH2Cl2 (100 mL). The filtrate was concentrated in vacuo to give 1.60 g of Compound #14 as a yellow oil (64%). 1H NMR (300 MHz, CDCl3): δ 7.80 (m, 1H), 7.35-7.21 (m, 8H), 3.81 (d, 2H), 3.35-3.26 (m, 2H), 3.22-3.13 (m, 2H), 2.16 (nonet, 1H), 0.95 (d, 6H) ppm. HPLC analysis (5:10:85 H2O:A1:MeOH) showed a purity of 96% with a retention time of 4.7 min.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]2[O:7][C:8]([CH3:11])([CH3:10])[O:9][C@@H:5]2[O:4][C@H:3]1[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.N1CCOCC1>O1CCCC1>[OH:1][C@H:2]1[C@@H:6]2[O:7][C:8]([CH3:10])([CH3:11])[O:9][C@@H:5]2[O:4][C@H:3]1[C:12]([N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)=[O:14]
Reactant: CN1CCOCC1
Reactant: CC1(C)O[C@@H]2O[C@@H](C(=O)O)[C@@H](O)[C@@H]2O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC1(C)O[C@@H]2O[C@@H](C(=O)N3CCOCC3)[C@@H](O)[C@@H]2O1
Reaction time: 1 h
Yield: 48 %

Procedure:
To a suspension of (3aS,5R,6S,6aS)-6-Hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxole-5-carboxylic acid (9.0 g, 44.2 mmol) and HBTU (25.1 g, 66.3 mmol, N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate) in tetrahydrofuran was added 4-methylmorpholine (7.3 mL, 66.3 mmol) at room temperature. After 1 h, morpholine (5.8 mL, 66.3 mmol) was added to the mixture at room temperature. After 12 h, the resulting mixture was filtered and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated in vacuo, and the crude was purified by silica gel column chromatography to provide the title compound (5.8 g, 48%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:21])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[NH:12][C:11](=S)[CH2:10][N:9]=1.CO[C:25](OC)([N:27](C)C)[CH3:26].[NH2:32]N>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:21])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[N:12]=[C:11]2[NH:32][NH:27][C:25]([CH3:26])=[C:10]2[N:9]=1
Reactant: COC(C)(OC)N(C)C
Reactant: NN
Reactant: COc1cc2c(cc1F)C(c1ccccc1Cl)=NCC(=S)N2
Product: COc1cc2c(cc1F)C(c1ccccc1Cl)=NC1=C(C)NNC1=N2

Procedure:
5-(2-chlorophenyl)-1,2-dihydro-7-fluoro-8-methoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVa) was prepared by reacting 0.0224 moles of 5-(2-chlorophenyl)-1,3-dihydro-7-fluoro-8-methoxy-2H-1,4-benzodiazepin-2-thione (IIa) with 1,1-dimethoxy-N,N-dimethyl-ethanamine and then hydrazine in a manner analogous to Example 55. MH+/Z=357.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([F:21])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:22])[CH2:4]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)[Cl:56]>CO>[ClH:56].[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH2:2][C@@H:3]3[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]4[C:20]5[C:15](=[N:16][CH:17]=[C:18]([F:21])[CH:19]=5)[CH:14]=[CH:13][C:12]4=[O:22])[CH2:4]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: NC[C@H]1CN(CCn2c(=O)ccc3ncc(F)cc32)C[C@H]1O
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Cl
Product: O=c1ccc2ncc(F)cc2n1CCN1C[C@H](CNCc2cc3c(cn2)OCCO3)[C@H](O)C1
Reaction time: 18 h
Yield: 28 %

Procedure:
1-{2-[(3S,4S)-3-(Aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one (110 mg, 0.359 mmol) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (65 mg; 0.395 mmol) were combined in anhydrous DCM (ml) and anhydrous MeOH (1 ml) with a spatula of solid sodium carbonate. The reaction mixture was stirred under nitrogen for 18 h then sodium triacetoxyborohydride (239 mg, 1.08 mmol) was added and stirred for 1 h. The reaction mixture was concentrated and purified to obtain the free base of the title compound as a pale yellow oil (46 mg, 28%) after column chromatography (90:10:1: DCM:MeOH:NH4OH).
Reaction SMILES: [I:1]C.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([NH:17][C:18](N)=[S:19])[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1>C(O)C>[IH:1].[N:17]([C:7]1[CH:8]=[CH:9][C:10]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]2)=[C:5]([O:4][CH3:3])[CH:6]=1)=[C:18]=[S:19]
Reactant: CI
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCO
Product: COc1cc(N=C=S)ccc1-n1cnc(C)c1
Product: I
Temperature: 50 °C
Yield: 33.8 %

Procedure:
Step D (5): Iodomethane (0.066 mL, 1.07 mmol) was added to a solution of 1-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)thiourea (280 mg, 1.07 mmol) in absolute ethanol (5 mL). The resulting mixture was heated at 50° C. for 3 h. After cooling to rt, the reaction was concentrated in vacuo. The crude residue was purified using silica gel chromatography (0-10% MeOH/chloroform, linear gradient over 72 min, flow 25 mL/min) to afford 1-(4-isothiocyanato-2-methoxyphenyl)-4-methyl-1H-imidazole hydroiodide (135 mg, 46% yield) as a white solid. LC-MS (M+H)+ 277.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][CH:11]=[C:10]3[N:14]([CH3:18])[N:15]=[C:16]([NH2:17])[C:9]=23)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([N:26]=[C:27]=[O:28])[CH:23]=[CH:22][C:21]=1[F:29].FC1C=CC(C)=CC=1N=C=O>>[NH2:17][C:16]1[C:9]2[C:10](=[CH:11][N:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:24]3[CH:23]=[CH:22][C:21]([F:29])=[C:20]([Cl:19])[CH:25]=3)=[O:28])=[CH:7][CH:6]=2)[N:14]([CH3:18])[N:15]=1
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Reactant: Cn1nc(N)c2c(-c3ccc(N)cc3)cncc21
Agent: Cc1ccc(F)c(N=C=O)c1
Product: Cn1nc(N)c2c(-c3ccc(NC(=O)Nc4ccc(F)c(Cl)c4)cc3)cncc21

Procedure:
The title compound was prepared using the procedure described in Example 1E using the product from Example 6A and 2-chloro-1-fluoro-4-isocyanato-benzene instead of the product from Example 1D and 1-fluoro-2-isocyanato-4-methyl-benzene. MS (ESI(+)) m/e 411 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 3.92 (s, 3H) 4.61-4.72 (m, 2H) 7.32-7.37 (m, 2H) 7.47 (d, J=8.82 Hz, 2H) 7.63 (d, J=8.82 Hz, 2H) 7.79-7.84 (m, 1H) 7.94 (s, 1H) 8.87 (s, 1H) 8.95 (s, 1H) 8.96 (s, 1H).
Reaction SMILES: C(Br)(Br)(Br)Br.[P:6]([O:11]C)([O:9][CH3:10])[O:7][CH3:8].[C:13]([O:17][C:18]([NH:20][C@@:21]([CH3:45])([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=2[O:40][CH2:41][O:42][CH3:43])=[CH:28][C:27]=1[Cl:44])[CH2:22][OH:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].O>N1C=CC=CC=1>[C:13]([O:17][C:18]([NH:20][C@@:21]([CH3:45])([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=2[O:40][CH2:41][O:42][CH3:43])=[CH:28][C:27]=1[Cl:44])[CH2:22][O:23][P:6]([O:9][CH3:10])([O:7][CH3:8])=[O:11])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: COP(OC)OC
Reactant: COCOc1ccc(C)cc1Sc1ccc(CC[C@@](C)(CO)NC(=O)OC(C)(C)C)c(Cl)c1
Agent: BrC(Br)(Br)Br
Solvent: O
Solvent: c1ccncc1
Product: COCOc1ccc(C)cc1Sc1ccc(CC[C@@](C)(COP(=O)(OC)OC)NC(=O)OC(C)(C)C)c(Cl)c1
Reaction time: 2 h

Procedure:
Carbon tetrabromide (130 mg) and trimethyl phosphite (46 μL) were added under ice cooling to a solution of the compound of Example 20 (97 mg) in pyridine (0.5 mL) to form a reaction solution. This reaction solution was stirred for 2 hours under ice cooling. Then, water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and then the solvent was removed by distillation under reduced pressure. The resultant product was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the target product (84 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4]([NH:16][CH2:17][CH2:18][CH3:19])[N:3]=1.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]1>>[ClH:1].[ClH:1].[NH2:20][CH:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:15][CH2:14][O:13][CH2:12]3)=[C:4]([NH:16][CH2:17][CH2:18][CH3:19])[N:3]=2)[CH2:23][CH2:22]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CCCNc1nc(Cl)nc2c1ncn2C1CCOC1
Product: CCCNc1nc(NC2CCC(N)CC2)nc2c1ncn2C1CCOC1
Product: Cl
Yield: 93.3 %

Procedure:
The operation is carried out as in Stage 3 of Example 2 starting from 109 mg of the product obtained in Stage 1 above and 445 mg of trans-1,4-diaminocyclohexane. After purification on silica eluting with methanol/ammonium hydroxide (NH4OH) in a proportion of 98/2, salification is carried out with 1.4 N hydrochloric acid in ethanol. In this way 78 mg of expected product is obtained in the form of crystals.
Reaction SMILES: [NH2:1][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.[C:16](OC(=O)C)(=[O:18])[CH3:17].C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[C:16]([NH: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)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine 4-aminobenzophenone (10.0 g, 50.8 mmol), acetic anhydride (5.74 mL, 60.9 mmol), and triethylamine (9.5 mL, 68.5 mmol) in toluene (30 mL). Heat to reflux. After 2 hours, cool to ambient temperature and pour the reaction mixture into water. Stir to give a solid. Collect the solid by filtration, rinse with water, and dry. Recrystallize from acetonitrile to give the title compound. Rf =0.35 (silica gel, ethyl acetate).
Reaction SMILES: ClC(O[CH2:5][C:6]1C=C[CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])=O.C([S:18][C@@H:19]1[CH2:23][N:22]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])[C@H:21]([C:37]([N:39]2[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][OH:47])[CH2:41][CH2:40]2)=[O:38])[CH2:20]1)(=O)C.[C:48]([O:51][CH2:52][CH3:53])(=[O:50])C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[SH:18][C@@H:19]1[CH2:23][N:22]([C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=2)=[O:25])[C@H:21]([C:37]([N:39]2[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][O:47][C:48]([O:51][CH2:52][C:53]3[CH:9]=[CH:8][C:7]([N+:12]([O-:14])=[O:13])=[CH:6][CH:5]=3)=[O:50])[CH2:41][CH2:40]2)=[O:38])[CH2:20]1
Reactant: CC(=O)S[C@H]1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C(Cl)OCc1ccccc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCCN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
A solution of 1.10 g of o-nitrobenzyl chloroformate in 10 ml of methylene chloride was added, whilst ice-cooling, to a solution of 1.63 g of (2S,4S)-4-acetylthio-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine and 0.62 g of 4-dimethylaminopyridine in 15 ml of methylene chloride and the resulting mixture was stirred at the same temperature for 2 hours. At the end of this time, the reaction mixture was diluted with 100 ml of ethyl acetate, and the dilute solution was washed, in turn, with 100 ml of an aqueous solution of sodium hydrogencarbonate, with 100 ml of water and with 100 ml of an aqueous solution of sodium chloride. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through slica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol ranging from 30:1 to 25:1 by volume as the eluent to give 1.86 g of the title compound, as a powder. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound thus obtained were identical with those of the compound prepared as described in step 90(b)(ii) above.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[C:29]1([CH2:35][CH:36]([OH:38])[CH3:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:26][C:23]1[C:22]([CH2:27][O:38][CH:36]([CH3:37])[CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:6]4([C:4]([OH:3])=[O:5])[CH2:8][CH2:7]4)=[CH:10][CH:11]=3)=[CH:20][CH:19]=2)[O:25][N:24]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Reactant: CC(O)Cc1ccccc1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1COC(C)Cc1ccccc1

Procedure:
Prepared according to the procedure described in Example 48, Step 2, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 1-phenyl-propan-2-ol.
Reaction SMILES: Cl.[C:2](=[NH:5])([NH2:4])[CH3:3].[C:6]([O-:9])(=O)[CH3:7].[Na+].C[N:12](C)[CH:13]=[O:14]>O>[CH3:2][CH:6]([O-:9])[CH3:7].[CH3:3][C:2]1[NH:5][C:13](=[O:14])[NH:12][N:4]=1
Reactant: CC(=O)[O-]
Reactant: CC(=N)N
Reactant: CN(C)C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)[O-]
Product: Cc1n[nH]c(=O)[nH]1
Temperature: 130 °C

Procedure:
A mixture of 40 parts of ethanimidamide hydrochloride, 20 parts of cis-N-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}hydrazinecarboxamide, 40 parts of sodium acetate and 90 parts of N,N-dimethylformamide is stirred and heated for 4 hours at 130° C. The reaction mixture is cooled and 100 parts of water are added. The precipitated product is filtered off, washed with water and with 2-propanol, and crystallized from 1-butanol, yielding 9 parts (44%) of cis-4-{4-[4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one 2-propanolate (2:1); mp. 295.7° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=2[CH3:16])[NH2:12])[CH:4]=1.[C:17]([O:21][C:22]([NH:24][C:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=S)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:31]([O:30][C:28]([NH:27][C:25]([NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[N:12][C:11]1[CH:13]=[CH:14][C:15]([CH3:16])=[C:9]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)[CH:10]=1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: COc1ccnc(-c2cc(N)ccc2C)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccnc(-c2cc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)ccc2C)c1
Reaction time: 2 h
Yield: 92.9 %

Procedure:
To a suspension of 3-(4-methoxypyridin-2-yl)-4-methylaniline (238 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (368 mg) and diisopropylethylamine (0.445 ml) in dichloromethane (10 ml) was added 1-methyl-2-chloropyridinium iodide (369 mg), and the mixture was stirred for 2 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, n-hexane:ethyl acetate=3:1) to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(4-methoxypyridin-2-yl)-4-methylphenyl)guanidine (471 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[CH:20][C:19]=3[O:31][CH3:32])[N:12]=2)[N:8]([CH3:33])[CH:7]=1)=[O:5])C.[OH-].[K+].[CH2:36](O)C>>[CH3:32][O:31][C:19]1[CH:20]=[C:21]([N:24]2[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]2)[CH:22]=[CH:23][C:18]=1[NH:17][C:13]1[N:12]=[C:11]([C:9]2[N:8]([CH2:33][CH3:36])[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[CH:10]=2)[CH:16]=[CH:15][N:14]=1
Reactant: CCO
Reactant: CCOC(=O)c1cc(-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3OC)n2)n(C)c1
Agent: [K+]
Agent: [OH-]
Product: CCn1cc(C(=O)O)cc1-c1ccnc(Nc2ccc(N3CCN(C)CC3)cc2OC)n1
Yield: 100 %

Procedure:
5-{2-[2-Methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (160 mg, 0.355 mmol) was suspended in ethanol (13 mL) and treated with a 1.5 M solution of potassium hydroxide in ethanol (2.4 mL, 10 eq.) at reflux temperature for 3 hour. Solvent was evaporated to dryness and the residue dissolved in water. After treatment with acetic acid and the resulting precipitate was collected by filtration to give the title compound (150 mg, 100% yield) as a white solid.
Reaction SMILES: [Na+].[CH3:2][O:3][N:4]=[C:5]([C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1)[C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:11]2[C:12]([C:24]([O-:26])=[O:25])=[C:13]([CH:16]=[CH:17][C:18]3[S:22][CH:21]=[N:20][C:19]=3[CH3:23])[CH2:14][S:15][C@H:10]12)=[O:7].[C:35]([O:41][CH2:42]I)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].C(OCC)(=O)C>CN(C)C=O>[C:35]([O:41][CH2:42][O:25][C:24]([C:12]1[N:11]2[C:27](=[O:28])[CH:9]([NH:8][C:6](=[O:7])[C:5](=[N:4][O:3][CH3:2])[C:29]3[N:30]=[C:31]([NH2:34])[S:32][CH:33]=3)[C@H:10]2[S:15][CH2:14][C:13]=1[CH:16]=[CH:17][C:18]1[S:22][CH:21]=[N:20][C:19]=1[CH3:23])=[O:26])(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=Cc3scnc3C)CS[C@H]12)c1csc(N)n1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(C=Cc3scnc3C)CS[C@H]12)c1csc(N)n1
Temperature: 0 °C

Procedure:
7-[2-Methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid sodium salt (syn-isomer, trans-isomer) (0.03 g, 0.06 mmol) was dissolved in dimethylformamide (3 ml). To the resultant solution was added a solution in dimethylformamide (1 ml) of iodomethyl pivalate (as prepared by reacting chloromethyl pivalate (0.090 g, 0.60 mmol) with sodium iodide (0.090 g, 0.06 mmol) in acetone) under ice-cooling, followed by stirring the resultant mixture for 10 minutes. The reaction solution as obtained were admixed with ice-water (20 ml) and ethyl acetate (20 ml), stirred thoroughly and then allowed to stand until the mixture separated into aqueous phase and organic phase. The organic phase was separated from the aqueous phase and washed twice with water (10 ml) and then with aqueous saturated NaCl solution (10 ml). The organic phase as washed was subsequently dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified chromatographically on a column of silica-gel (Wako-gel C-300) (5 g) as developed with ethyl acetate. The titled compound was thus obtained (yield 0.025 g, 67%).
Reaction SMILES: C(O)(=O)C(O)=O.[CH3:7][O:8][CH2:9][CH2:10][NH:11][NH2:12].[CH3:13][C:14]([CH3:21])([CH3:20])[C:15](=O)[CH2:16][C:17]#[N:18]>C(O)C>[C:14]([C:15]1[CH:16]=[C:17]([NH2:18])[N:11]([CH2:10][CH2:9][O:8][CH3:7])[N:12]=1)([CH3:21])([CH3:20])[CH3:13]
Reactant: COCCNN
Reactant: CC(C)(C)C(=O)CC#N
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: COCCn1nc(C(C)(C)C)cc1N
Temperature: 85 °C
Yield: 98.5 %

Procedure:
A stirred suspension of (2-methoxyethyl) hydrazine oxalic acid (0.50 g, 2.77 mmol) and 4,4-dimethyl-3-oxopentanenitrile (0.347 g, 2.77 mmol) in ethanol (6 mL) was heated at 85° C. for 4.5 h during which time all solids dissolved. The reaction mixture was allowed to cool overnight and then the solvent was evaporated. The residue was dissolved in dichloromethane (20 mL) and washed with saturated aqueous NaHCO3 (10 mL). The organic layer was separated using a phase separator cartridge and evaporated. The residual oil was dissolved in diethyl ether and evaporated to afford the title compound (0.538 g, 98%) as a solid. 1H NMR (300 MHz, CDCl3): 1.26 (9H, s), 3.33 (3H, s), 3.67 (2H, t, J 4.3 Hz), 3.95 (2H, br s), 4.13 (2H, t, J 4.6 Hz), 5.36 (1H, s).
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@:4]1([CH3:22])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:21])[CH2:6][CH2:5]1.[CH3:23]OC(OC)(C)C.[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.N1C=CC=CC=1>C(OCC)(=O)C>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@:4]1([CH3:22])[C:9](=[CH:10][CH2:11]2)[CH:8]=[C:7]([O:21][CH3:23])[CH2:6][CH2:5]1
Reactant: COC(C)(C)OC
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](F)C[C@]2(C)C(=O)CC[C@@H]12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC1=CC2=CC[C@@H]3[C@H]([C@@H](F)C[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Reaction time: 8 h

Procedure:
10.0 g of 11β-fluoroandrost-4-ene-3,17-dione [U.S. Pat. No. 3,966,713 (1976)] is stirred under reflux with 60 ml of dimethoxypropane and 1.0 g of pyridinium-4-toluenesulfonate. After 8 hours, 1 ml of pyridine is added, the mixture is diluted with ethyl acetate, washed neutral with water, and dried. The crude product is chromatographed on silica gel with an acetone-hexane gradient. Yield: 7.8 g of 11β-fluoro-3-methoxyandrosta-3,5-diene-17-one as a foam.