Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH:5]([OH:10])[CH2:6][CH2:7][CH2:8][Cl:9].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH:5]([O:10][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:6][CH2:7][CH2:8][Cl:9]
Reactant: COC(=O)CC(O)CCCCl
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CC(CCCCl)OS(C)(=O)=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
In an atmosphere of nitrogen, 6-chloro-3-hydroxy-hexanoic acid methyl ester (2); 66.5 g {(GC purity; 79.1%, pure amount; 52.6 g (0.295 mol)}, triethylamine (44.7 g, 0.443 mol) and toluene (250 ml) were added to a 500 ml capacity flask, followed by cooling to 5° C. Methanesulfonyl chloride (37.0 g, 0.325 mol) was added dropwise thereto, followed by stirring at 5° C. for 0.5 hour to obtain a toluene solution of 6-chloro-3-methanesulfonyloxy-hexanoic acid methyl ester (3).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:18][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][C:15](=[O:24])[CH:14]=2)=[CH:9][CH:8]=1.O>ClCCl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:18][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][C:15](=[O:24])[CH:14]=2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1cc(=O)cc(-c2ccc(OC)cc2)o1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc(=O)cc(-c2ccc(O)cc2)o1
Reaction time: 2 h

Procedure:
Boron tribromide (5.0 g) was added dropwise to a stirred solution of ethyl 6-(4-methoxyphenyl)-4-oxo-4H-pyran-2-carboxylate (5.48 g) in dichloromethane (40 ml) cooled to 0°-5° C. After 2 hours at below 5° C., water was cautiously added to the reaction mixture, with cooling, and the yellow solid which precipitated was filtered off. Recrystallisation from ethanol and then from ethyl acetate gave the title product as yellow crystals (mp 213°-215° C.).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]1[C:19]2[CH:18]([CH2:20][O:21][C:22](Cl)=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.[Cl:25][C@@H:26]1[CH2:30][NH:29][C@@H:28]2[C@@H:31]([OH:34])[CH2:32][O:33][C@H:27]12>O.O1CCOCC1>[Cl:25][C@@H:26]1[CH2:30][N:29]([C:22]([O:21][CH2:20][CH:18]2[C:19]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:16]3[C:17]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:23])[C@@H:28]2[C@@H:31]([OH:34])[CH2:32][O:33][C@H:27]12
Reactant: O[C@H]1CO[C@H]2[C@@H]1NC[C@H]2Cl
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1C[C@@H](Cl)[C@H]2OC[C@H](O)[C@H]21
Reaction time: 1.08 h
Yield: 76 %

Procedure:
A solution of sodium carbonate (155 mg, 1.46 mmol) in water (2.5 mL) then a solution of 9-fluorenylmethoxycarbonyl chloride (189 mg, 0.73 mmol) in 1,4-dioxane (1.5 mL) was added whilst stirring to a solution of aminoalcohol (77) in 1,4-dioxane (1 mL). The mixture was stirred for 65 minutes then water (20 mL) was added and the product extracted into dichloromethane (3×10 mL), then dried (Na2SO4), filtered and reduced in vacuo to leave a residue. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 10:90 to 50:50 gave alcohol (78) (194 mg, 76%) as a white solid. TLC (Rf=0.45, EtOAc:heptane 1:1), analytical HPLC single main peak, Rt=15.51 min., HPLC-MS 386.1/388.1 [M+H]+, 408.1/410.1 [M+Na]+; [α]D23.0−7.46° (c=2.01, CHCl3); δH (500 MHz, CDCl3) mixture of rotamers 1:1; 1.15 (0.5H, s, OH), 3.05 (0.5H, t, J=9.58 Hz, FmocNCH2), 3.09 (0.5H, s, OH), 3.23 (0.5H, t, J=10.38 Hz, FmocNCH2), 3.43 (0.5H, d, J=4.37 Hz, FmocNCH), 3.53 (0.5H, brs, OCH2CHOH), 3.62 (0.5H, dd, J=10.20 and 1.92 Hz, OCH2CHOH), 3.75 (0.5H, dd, J=10.21 and 4.53 Hz, OCH2CHOH), 3.84-3.97 (2H, m, 1×FmocNCH2, 0.5×OCH2CHOH and 0.5×CHCl), 4.02 (0.5H, dd, J=9.96 and 4.65 Hz, OCH2CHOH), 4.06-4.12 (0.5H, m, CHCl), 4.15-4.26 (1.5H, m, Fmoc CH and 0.5×FmocNCH), 4.39-4.46 (1.5H, m, 0.5×OCH2CHOH, 0.5×Fmoc CH2 and 0.5×CHCHCl), 4.50 (0.5H, dd, J=10.64 and 6.70 Hz, Fmoc CH2), 4.67 (0.5H, t, J=4.29 Hz, CHCHCl), 4.75 (0.5H, dd, J=10.86 and 3.69 Hz, Fmoc CH2), 4.82 (0.5H, dd, J=10.82 and 3.97 Hz, Fmoc CH2), 7.30-7.81 (8H, aromatic CH); δC (125 MHz, CDCl3) 47.22/47.41 (Fmoc CH), 50.55/50.93 (FmocNCH2), 54.60/55.28 (CHCl), 65.94/67.60 (Fmoc CH2), 69.08/69.56 (FmocNCH), 75.00/75.35 (OCH2CHOH), 76.23/76.86 (OCH2CHOH), 81.27/81.84 (CHCHCl), 119.87/119.92/120.09/124.42/124.46/124.82/124.88/127.10/127.50/127.51/127.89/127.96/127.98/128.53 and 128.65 (aromatic CH), 141.24/141.36/141.44/143.44/143.57/143.83 and 143.84 (aromatic quaternary), 153.41/154.42 (Fmoc C═O).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[C:10]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([NH:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:19][CH2:20]2)[C:10]1=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(N=C2CCN(c3ccncc3)CC2)C1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(NC2CCN(c3ccncc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
(3S)-3-(tert-Butoxycarbonylamino)-1-[1-(4-pyridyl)-4-piperidinylideneamino]-2-pyrrolidone (3.57 g) was dissolved in methanol (40 ml), combined with acetic acid (2.05 g) with cooling on ice, followed by sodium cyanoborohydride (807 mg) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was combined with an aqueous solution of sodium hydroxide, extracted with dichloromethane, dried, concentrated, and purified by a column chromatography (dichloromethane: 10% aqueous ammonia-containing methanol=20:1) to obtain the title compound (2.56 g) as a colorless amorphous material.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](O)=[CH:3][CH:2]=1.O.[NH2:13][NH2:14].N>Cl>[NH:13]1[CH:2]=[CH:3][C:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:1])=[N:14]1
Reactant: NN
Reactant: Oc1ccnc2ccccc12
Agent: Cl
Agent: N
Solvent: O
Product: Nc1ccccc1-c1cc[nH]n1

Procedure:
1.1. 10.0 g of 4-quinolinol in 30g of hydrazine hydrate are heated to 170° C. in an autoclave for 6 h. After cooling, the reaction mixture is dissolved in aqueous hydrochloric acid (total volume of the solution about 300 ml, pH about 1). Then, the mixture is made slightly alkaline (pH about 9) with concentrated aqueous ammonia solution. The separated crystals are filtered off and dried. There are obtained 8.0 g of 2-(1H-pyrazol-3-yl)aniline of m.p. 122°-123° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl.Cl.N1CCNCC1>O>[Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CNCCN1
Reactant: Clc1ncccc1Br
Agent: Cl
Solvent: O
Product: Brc1cccnc1N1CCNCC1
Temperature: 190 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
Add 3-bromo-2-chloro-pyridine (10.08 g, 52.4 mmol) to piperazine (45 g) and piperazine dihydrochloride (83.4 g). Heat the mixture to 190° C. with stirring for one hr. Allow the mixture to cool to about 80° C. then pour the material into water and extract 5 times with DCM. Dry the solution (sodium sulfate), filter and concentrate. Purify using silica gel chromatography, eluting with 15:85 methanol (with 2 M ammonia): DCM to give 1-(3-bromo-pyridin-2-yl)-piperazine as a white solid (8.98 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13]([OH:15])=[O:14])=[C:7]2[OH:12].Cl[S:17]([C:20]1[CH:21]=[C:22]([S:28]([F:31])(=[O:30])=[O:29])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27])(=[O:19])=[O:18].CN(C)C1C=CC=CC=1.Cl>CN(C)C(=O)C>[F:31][S:28]([C:22]1[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:20]([S:17]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:13]([OH:15])=[O:14])=[C:7]3[OH:12])(=[O:18])=[O:19])[CH:21]=1)(=[O:29])=[O:30]
Reactant: COc1ccc(S(=O)(=O)F)cc1S(=O)(=O)Cl
Reactant: Nc1cccc2c(O)c(C(=O)O)ccc12
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: CC(=O)N(C)C
Product: COc1ccc(S(=O)(=O)F)cc1S(=O)(=O)Nc1cccc2c(O)c(C(=O)O)ccc12
Temperature: 22 °C
Reaction time: 16 h
Yield: 36.4 %

Procedure:
5-Amino-1-hydroxy-2-naphthoic acid (10.2 g, 50 mmol) and 3-chlorosulfonyl-4-methoxybenzenesulfonylfluoride (14.4 g, 50 mmol) as prepared as in 1A were suspended in N,N-dimethylacetamide (100 ml). N,N-Dimethylaniline (15.1 g, 125 mmol) was added, the mixture was stirred at room temperature (22° C.) for 16 hours, and was then poured into ice water (750 ml) acidified with concentrated hydrochloric acid (25 ml). The mixture was extracted with three portions of ethyl acetate (500 ml each). The combined extracts were dried over anhydrous magnesium sulfate, the salts were removed by filtration, and the filtrate was decolorized with acidic alumina. The alumina was separated and the solvent was removed under reduced pressure to yield 8.3 g, (36.4%) of product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](Cl)=[N:8][CH:9]=1)([O-:3])=[O:2].[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]([NH2:19])=[O:18])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([NH2:19])=[O:18])[CH2:13][CH2:12]2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(=O)C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)C1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 100 °C
Yield: 92.9 %

Procedure:
A mixture of 5-nitro-2-chloro-pyridine (2 g, 12.6 mmol), piperidine-4-carboxylic acid amide (1.78 g, 13.9 mmol), and potassium carbonate (3.48 g, 25.2 mmol) in anhydrous 1,4 dioxane (65 mL) was heated in an oil bath at 100° C. for 5 hr. The reaction was diluted with water (500 mL) and extracted with ethyl acetate (500 mL). The resulting yellow precipitate that form in both layers was filtered off and washed with minimal ethyl acetate, dichloromethane, and hexanes, and dried. The aqueous layer was extracted with dichloromethane (three times with 200 mL each). This dichloromethane layer was washed with brine, combined with the original ethyl acetate extract dried over sodium sulfate, and concentrated to a yellow solid. The yellow solid and the original yellow filtered precipitate were combined to give 5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid amide (2.93 g, 112%) as a yellow solid. LCMS calcd for C11H14N4O3 (m/e) 250, obsd 251 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH2:12][O:13][CH2:14][C:15]2([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[N:3]=1.[CH:29]1(B(O)O)[CH2:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH:29]1([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH2:12][O:13][CH2:14][C:15]3([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[N:3]=2)[CH2:31][CH2:30]1
Reactant: CN1CCC(COCc2cc(C(F)(F)F)cc(Cl)n2)(c2ccc(F)cc2)CC1
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CN1CCC(COCc2cc(C(F)(F)F)cc(C3CC3)n2)(c2ccc(F)cc2)CC1
Temperature: 100 °C
Yield: 68.3 %

Procedure:
2-chloro-6-(((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-4-(trifluoromethyl)pyridine (50 mg, 0.120 mmol), cyclopropylboronic acid (30.9 mg, 0.360 mmol) PdCl2(dppf)-CH2Cl2Adduct (9.80 mg, 0.012 mmol), cesium carbonate (121 mg, 0.372 mmol) were combined in toluene (1 ml). The reaction was flushed with nitrogen and heated to 100° C. for 2 hours. After cooling, the reaction was quenched with 10 ml saturated sodium bicarbonate, and diluted with ethyl acetate. The organics were then washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified via preparatory HPLC and the desired product (34.8 mg, 0.082 mmol, 68.7%) was submitted as the TFA salt. 1H-NMR (CD3OD, 400 MHz) δ 7.48 (m, 2H), 7.33 (m, 1H), 7.14 (t, 2H), 7.08 (m, 1H), 4.47 (m, 2H), 3.46 (m, 4H), 2.84 (m, 2H), 2.74 (s, 3H), 2.67 (m, 2H), 2.13 (m, 3H), 0.97 (m, 4H). LC: Tr=1.850 min, HPLC Method 1. Mass spec.: 423.27 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10].C([Mg]Cl)(C)C.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[F:10])([OH:29])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc(Br)c(F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCN(Cc3ccccc3)CC2)c(F)c1
Temperature: 0 °C

Procedure:
To a stirred and cooled (0° C.) solution of 4-bromo-3-fluoroanisole (1 g; 4.88 mmol) in anhydrous THF (7 mL) was added isopropyl magnesium chloride (2.0M in THF; 2.22 mL; 4.43 mmol) dropwise. The reaction was stirred at room temperature for 30 min and then cooled to 0° C. 1-benzyl-4-piperidone (0.72 mL; 4.03 mmol) was added dropwise and the reaction was stirred at room temperature for 14 h. The reaction was quenched with saturated NH4Cl and partitioned between EtOAc (50 mL) and H2O (30 mL). The aqueous layer was extracted with EtOAc (3×50 mL) and the combined extracts were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-50% EtOAc/hexanes gradient) to afford 1-benzyl-4-(2-fluoro-4-methoxyphenyl)piperidin-4-ol as a light orange solid. LCMS=315.9 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.38-7.31 (m, 5H), 7.28-7.24 (m, 1H), 6.66 (dd, J=8.7, 2.5 Hz, 1H), 6.61 (dd, J=14.4, 2.5 Hz, 1H), 3.79 (s, 3H), 3.56 (s, 2H), 2.77 (br d, J=10.6 Hz, 2H), 2.54-2.48 (m, 2H), 2.31-2.24 (m, 2H), 1.84 (d, J=12.3 Hz, 2H).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([CH:9]2[O:14][CH2:13][CH2:12][O:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1)N.[H][H]>[Ni].C(O)C>[NH2:1][C:3]1[CH:8]=[C:7]([CH:9]2[O:14][CH2:13][CH2:12][O:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1
Reactant: NNc1cc(C2COCCO2)ccn1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(C2COCCO2)ccn1
Reaction time: 4 h

Procedure:
A mixture of 9.56 g. (49 mmoles) of 1-(2-hydrazino-4-pyridyl)-1-ethylenedioxyethane and 35 g. of Raney nickel in 150 ml. of absolute ethanol was shaken in a hydrogen atmosphere at an initial pressure of 3 atms. at room temperature for 4 hours. The catalyst was filtered and the filtrate concentrated to give 1-(2-amino-4-pyridyl)-1-ethylenedioxyethane as a white solid, m.p. 123°-126° C. The residual material was dissolved in 60 ml. of 2 N hydrochloric acid and heated at 75° C. for 3 hours. The mixture was cooled, neutralized with sodium bicarbonate and extracted with chloroform (30 ml.×6). The combined extracts were dried and concentrated to give a pale yellow solid, which on recrystallization from toluene gave 5.0 g. (75%) of 1-(2-amino-4-pyridyl)-1-ethanone, m.p. 133°-133.5° C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([O:12][C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)[CH:7]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([O:12][C:13]2[CH:19]=[CH:18][C:16]([N:17]=[C:1]=[O:2])=[CH:15][CH:14]=2)[N:9]=[CH:10][N:11]=1
Reactant: Nc1ccc(Oc2cc(Cl)ncn2)cc1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(Oc2cc(Cl)ncn2)cc1
Temperature: -20 °C

Procedure:
Apparatus: 2 litre 3-neck-roundbottle flask, dropping funnel, short Vigreux column and condenser. A phosgene solution (20% in toluene, 118 ml; 223 mmol) diluted with toluene (800 ml) under N2-atmosphere is cooled to approximately −20° C. Then a solution of 4-(6-chloro-pyrimidin-4-yl-oxy)-aniline (Stage 21.1; 18.52 g, 83.6 mmol) in CH2Cl2 (400 ml) is added dropwise. The resulting suspension is heated to distil off approximately 400 ml of solvent. Distillation Is continued (boiling point: 110° C.), while a mixture of phosgene solution (20% in toluene, 59 ml) and toluene (500 ml) is added dropwise, followed by toluene (250 ml). The resulting clear solution (a 250 ml) in the reaction vessel is cooled to rt, filtered and the filtrate concentrated in vacuo. Distillation of the resulting waxy crude product on the Kugelrohr apparatus (0.2 mbar, 200° C.) gives the title compound as a solid: m.p.: 103° C.; MS: [M+1]+=302; 1H-NMR (CDCl3): 8.57 (s, 1H), 7.17 (d, 2H), 7.10 (d, 2H), 6.95 (s, 1H).
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:35])[C@H:20]2[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([SH:47])[CH2:44][C@H:43]1[CH:48]1[CH2:52][C:51](=[O:53])[NH:50][C:49]1=[O:54])=[O:41])[CH:37]=[CH2:38]>>[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([S:47][C:18]2[C@H:19]([CH3:35])[C@@H:20]3[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]3[C:22]=2[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH2:44][C@H:43]1[CH:48]1[CH2:52][C:51](=[O:53])[NH:50][C:49]1=[O:54])=[O:41])[CH:37]=[CH2:38]
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1C1CC(=O)NC1=O
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C3CC(=O)NC3=O)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 50.9 %

Procedure:
The same procedure as in Example 8-1 was carried out by using allyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (230 mg, 0.46 mmol) and (2S,4S)-N-allyloxycarbonyl-2-(2,5-dioxopyrrolidin-3-yl)-4-mercaptopyrrolidine (130 mg, 0.46 mmol, compound of Reference Example 9) to obtain allyl (1R,5S,6S)-2-[(2S,4S)-N-allyloxycarbonyl-2-(2,5-dioxopyrrolidin-3-yl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (125 mg, yield: 50.9%).
Reaction SMILES: CN(C)C=O.[C:6]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)(=O)[CH3:7].[Br-].[CH2:16]([O:23][C:24]([CH2:26][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[N:12]1[CH:13]=[CH:14][C:9]([C:6]([CH3:7])=[CH:26][C:24]([O:23][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:25])=[CH:10][CH:11]=1
Reactant: CC(=O)c1ccncc1
Reactant: O=C(C[P+](c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=CC(=O)OCc1ccccc1)c1ccncc1
Temperature: 70 °C
Yield: 42.4 %

Procedure:
N,N-Dimethylformamide (33 ml) was added to a mixture of 4-acetylpyridine (2.00 g, 16.5 mmol) and (benzyloxycarbonyl)methyltriphenylphosphonium bromide (8.94 g, 18.2 mmol), and the whole was stirred under ice-cooling. Potassium carbonate (9.12 g, 66.0 mmol) was added thereto, the external temperature was raised to 70° C., and the whole was stirred overnight. The reaction mixture was diluted with diethyl ether (100 ml), and the whole was washed with water (100 ml, twice) and saturated brine (50 ml) successively. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1.77 g (42%: mixture of E form and Z form) of benzyl 3-(4-pyridyl)-2-butenoate as a pale yellow oily matter.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=[O:13].[OH-].[Na+]>CO.O>[CH3:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)c1ccc2c(c1C)OCCS2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)ccc2c1OCCS2
Reaction time: 2 h

Procedure:
4.0 g (0.0168 mol) of ethyl 8-methyl-2,3-dihydrobenz-1,4-oxathiine-7-carboxylate together with 1.0 g (0.0252 mol) of sodium hydroxide are refluxed in 40 ml of methanol/water. The mixture is stirred for 2 hours at this temperature, and the solvent is subsequently distilled off. The residue is taken up in water. The mixture is extracted using ether, and the aqueous phase is then acidified using 2 N hydrochloric acid. The product of value precipitates and is filtered off with suction and washed with a small amount of water. The product is dried in a vacuum drying oven at 40° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][CH2:5]O>>[CH3:1][N:2]([CH3:1])[C@@H:3]1[CH2:4][CH2:5][CH2:5][CH2:4][C@H:3]1[NH2:2]
Reactant: CNC
Reactant: CCO
Product: CN(C)[C@@H]1CCCC[C@H]1N
Reaction time: 19 h

Procedure:
A solution of the benzylamino compound was hydrogenated in two batches each containing 30.5 g. (0.131 mole), 175 ml. EtOH, 3.5 g Pd--C and 56.5 g. (0.394 mole) of 70% HClO4, at initial pressure of 51.5 p.s.i. for 19 hours. The two batches were combined, filtered through Celite and evaporated in vacuo at 45°. The residue was cooled in ice, basified with 40% KOH to pH 11. The resulting thick suspension was extracted with ether (5×200 ml), the ether extract was dried (MgSO4) and evaporated through a 9" Vigreux. The residue was distilled at 13 mm to give 32.5 g. (87% yield), b.p. 77°-78.5°. Vpc 100% at 3.8 mm. ir and nmr was identical to those of the sample prepared by the reaction of 7-azabicyclo[3.1.0]heptane with dimethylamine.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>>[CH3:11][Si:12]([C:15]#[C:16][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)([CH3:14])[CH3:13]
Reactant: Ic1ccc2[nH]ncc2c1
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1ccc2[nH]ncc2c1
Yield: 45.8 %

Procedure:
In an adaption of GP 8a, 5-Iodo-1H-indazole (0.98 g, 4.02 mmol) was reacted with trimethylsilyl acetylene (0.60 mL, 4.22 mmol) at 90° C. for 5 h to give 395 mg (46%) of pure 5-(trimethylsilyl)ethynyl-1H-indazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([O:16][C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:13][NH:12]2)=[O:10])=[CH:4][CH:3]=1.[O:25]([C:32]1[N:37]=[C:36]([C:38](Cl)=[O:39])[CH:35]=[CH:34][N:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[OH-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([O:16][C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:13][N:12]2[C:38]([C:36]2[CH:35]=[CH:34][N:33]=[C:32]([O:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:37]=2)=[O:39])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccnc(Oc2ccccc2)n1
Reactant: O=C(OC1CNN(C(=O)Cc2ccc(F)cc2)C1)N1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(OC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)c2ccnc(Oc3ccccc3)n2)C1)N1CCOCC1
Reaction time: 12 h
Yield: 61 %

Procedure:
Morpholine-4-carboxylic acid 1-[2-(4-fluorophenyl)acetyl]-pyrazolidin-4-yl ester, 41, (354 mg, 1.05 mmol) and 2-phenoxypyrimidine-4-carbonyl chloride, 18, (345 mg, 1.47 mmol) are dissolved in dichloromethane (2 mL). 1.0 N NaOH (3 mL) is added dropwise at room temperature while vigorously stirring. The reaction is allowed to proceed for 12 hours after which time additional acid chloride, 18, is added and stirring continued for 3 hours. Additional acid chloride, 18, (83 mg) is added and stirring continued for an additional 12 hours. After which time the reaction is diluted with dichloromethane (50 mL) and washed with water (50 mL). The combined organic layers are washed with NaHCO3 (sat.) (50 mL) and brine (50 mL), dried, filtered and concentrated to provide a brown oil. The crude material is purified over silica (100% ethyl acetate to 5% methyl alcohol/ethyl acetate) afford 348 mg (61% yield) of the desired product as a viscous oil.