Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([N:21]=[CH:22][CH:23]=2)[CH:12]=[C:13]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)[CH:14]=1)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[CH3:20][N:18]1[CH:19]=[C:15]([C:13]2[CH:14]=[C:9]([OH:8])[C:10]3[N:11]([N:21]=[CH:22][CH:23]=3)[CH:12]=2)[CH:16]=[N:17]1
Reactant: Cn1cc(-c2cc(OCc3ccccc3)c3ccnn3c2)cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cn1cc(-c2cc(O)c3ccnn3c2)cn1
Reaction time: 2 h

Procedure:
4-(benzyloxy)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (185 mg, 0.608 mmol) and palladium hydroxide on carbon (85 mg, 0.122 mmol, 20 wt %) were suspended in EtOH (10 ml) and placed under an atmosphere of hydrogen (balloon). After 2 h, additional palladium hydroxide on carbon (85 mg, 0.122 mmol, 20 wt %) was added and the mixture was allowed to stir overnight. The reaction mixture was filtered through a 45 μm syringe filter and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (methanol/ethyl acetate gradient) to afford 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[N:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1>N.[Ni]>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([O:8][C:9]2[N:14]=[C:13]([CH2:15][NH2:16])[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(Oc2cccc(C#N)n2)CC1
Agent: [Ni]
Agent: N
Product: CN1CCC(Oc2cccc(CN)n2)CC1

Procedure:
6-[(1-Methylpiperidin-4-yl)oxy]pyridine-2-carbonitrile (1.62 g, 7.46 mmol, from step a above) was dissolved in 150 mL of ammonia saturated MeOH and hydrogenation was performed using a Raney-Ni 30×4 mm CatCart (H-Cube, 50 bar, 50° C., 1 mL/min). The mixture was evaporated and was pure enough to use directly in the next step below. Yield: 1.62 g (98%). 1H NMR (500 MHz, CDCl3) δ 7.50 (m, 1H), 6.75 (d, 1H), 6.56 (d, 1H), 5.11 (m, 1H), 3.82 (s, 2H), 2.74 (m, 2H), 2.43-2.30 (m, 5H, thereof a singlet at 2.34), 2.07 (m, 2H), 1.87 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH3:13])[CH3:12].[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C(COC)OC.O.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.CCOC(C)=O>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[C:5]3([CH3:13])[CH3:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CC1(C)C(=O)Nc2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(-c2ccc3c(c2)C(C)(C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.8 %

Procedure:
5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (0.33 g, 1.38 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.094 g) were stirred under an atmosphere of nitrogen in dimethoxyethane (12 cm3). After 15 minutes, 3-methoxyphenylboronic acid (0.42 g, 2.76 mmol) was added, followed by potassium carbonate (1.15 g, 8.34 mmol) in water (5 cm3). The reaction was heated to reflux for 5 hours, and then cooled to room temperature. Saturated aqueous ammonium chloride and EtOAc were added and the mixture was filtered. The aqueous layer was extracted with EtOAc (×2), and the combined organic layers were dried (MgSO4), filtered, and evaporated. The residue was purified by column chromatography (SiO2, EtOAc: hexane 1:3) to afford 5-(3-methoxy-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one (0.11 g, 31%), mp=157-158° C.; 1H NMR (DMSO-d6) δ3.34 (s, 6H), 3.82 (s, 3H), 6.87-6.93 (m, 2H), 7.20-7.15 (m, 2H), 7.37-7.32 (m, 1H), 7.49-7.46 (m, 1H), 7.63 (d, 1H, J=1.14 Hz), 10.4 (s, 1H); MS (EI) m/z 266 (M−H)−; CHN calculated for C17H17NO2: C, 76.38; H, 6.41; N, 5.24; Found: C, 76.02; H, 6.49; N, 5.02.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15](OC(C)(C)C)=O)[CH:5]=[N:6][CH:7]=1.C(O)=O.C=O.C([O-])([O-])=O.[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Cl)c1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Product: CN1CCC[C@H]1COc1cncc(Cl)c1
Yield: 62.9 %

Procedure:
To 5-chloro-3-((1-t-butoxycarbonyl-2-(S)-pyrrolidinyl)methoxy)pyridine (0.600 g, 1.92 mmol), from Example 15b, was added a solution of formic acid/formaldehyde (1:2,3 mL). The mixture was heated at reflux for 3 hours, then basified with sat. K2CO3. The aqueous phase was extracted with CH2Cl2 (3×) then the organic layer was dried (MgSO4) and concentrated. The crude product was purified by chromatography over silica gel eluted with CHCl3/MeOH to afford 0.274 g (63%) of the title compound as a pale yellow oil. TLC Rf =0.23 (10%MeOH/CHCl3). MS (DCI/NH3) m/e: 227 (M+H)+ with 35Cl and 229 (M+H)+ with 37Cl. 1H NMR (CDCl3, 300 MHz) δ: 8.22 (d, J=2.6 Hz, 1H), 8.19 (d, J=2.2 Hz, 1H), 7.22 (t, J=2 Hz, 1H), 4.00 (dd, J=9, 5.50 Hz, 1H), 3.92 (dd, J=9, 5.20 Hz, 1H), 3.14-3.08 (m, 1H), 2.69-2.64 (m, 1H), 2.47 (s, 3H), 2.36-2.27 (m, 1H), 2.07-1.97 (m, 1H), 1.88-1.69 (m, 3H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH:20]([C:21]([O:23]C(C)(C)C)=[O:22])[CH2:19][CH2:18][NH:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)[C:31]([OH:33])=[O:32]>>[C:1]1([CH2:7][O:8][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH:20]([C:21]([OH:23])=[O:22])[CH2:19][CH2:18][N:17]2[C:31]([O:33][C:1]([CH3:7])([CH3:6])[CH3:2])=[O:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C1CCNC1CCCCCCC(=O)OCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1CCCCCCC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
The product of Example 17 is dissolved in trifluoroacetic acid and the solution is stored at room temperature for one hour. The mixture is then concentrated to dryness in vacuo, and the residue is acylated with t-butyloxycarbonyl azide by the procedure described in Example 13 to obtain 3-carboxy-1-[(t-butyloxy)carbonyl]-2-pyrrolidineheptanoic acid phenylmethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2=[N:15][C:16](S(C)(=O)=O)=[N:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:13]2[CH2:12][NH:11][C:10]1=[O:31].[CH3:32][CH2:33][O-:34].[Na+]>CCO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2=[N:15][C:16]([O:34][CH2:33][CH3:32])=[N:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:13]2[CH2:12][NH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(-c2ccc(F)cc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2

Procedure:
The product of Example 3 (0.0658 g, 0.147 mmol) was suspended in EtOH (2 mL) and stirred under argon. A 0.5 M solution of NaOEt in EtOH (0.587 mL, 0.294 mmol) was added. After 15 min the solvent was removed in vacuo, and the residue partitioned between EtOAc and H2O. The organic phase was washed with H2O (2×), satd aq NaCl (1×), dried over anhydrous Na2SO4, filtered, and evaporated to give the crude product. Flash chromatography on silica gel eluted with 0-5% EtOAc/CH2Cl2 gave the title compound as a white-amorphous solid. mp 191-194° C., LC MS m/z=415 (MH+) Rt=2.15 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=2)[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(CO)cc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccc(CO)cc2)cc1N
Reaction time: 23.5 h
Yield: 108.1 %

Procedure:
{4-[(3,4-dinitrophenyl)oxy]phenyl}methanol (3.73 g, 12.9 mmol) was hydrogenated in approximately 100 ml of ethyl acetate under a balloon of hydrogen over 1.2 g of 10% Pd on carbon (wet, degussa type) for 2.5 hours. An additional 600 mg of 10% Pd on carbon (wet, degussa type) was added and the reaction was hydrogenated under a balloon of hydrogen for 14.5 hours. The catalyst was filtered away and the filtrate was concentrated. The residue was dissolved in 1:1 ethanol:ethyl acetate and hydrogenated under a balloon of hydrogen over 1.2 g of 10% Pd on carbon (wet, degussa type) for 23.5 hours to consume remaining reaction intermediates. The catalyst was filtered away and the filtrate was concentrated to give 3.21 g of crude {4-[(3,4-diaminophenyl)oxy]phenyl}methanol, which was used without further purification.
Reaction SMILES: [CH2:1]([Si:8]([CH3:13])([CH3:12])[CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([Si:8]([CH3:13])([CH3:12])[CH2:9][CH2:10][N:18]1[C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]2[C:14]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[Si](C)(CCO)Cc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[Si](C)(CCN1C(=O)c2ccccc2C1=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
A mixture of β-(benzyldimethylsilyl)ethanol (0.84 g, 4.33 mmol), phthalimide (0.66 g, 4.5 mmol), diethylazodicarboxylate (0.783 g, 4.5 mmol) and triphenylphosphine (1.18 g, 4.5 mmol) in anhydrous tetrahydrofuran (80 ml) is stirred, under nitrogen, at room temperature for 18 hours. The solvent is removed in vacuo. The residue is taken off in toluene and the insoluble material is filtered off. The filtrate is evaporated to dryness. The residue is taken off in diethyl ether and the insoluble material is filtered off. The solvent is removed in vacuo. Chromatography (silica gel, hexane/diethyl ether-80/20) affords the title compound (0.94 g, 67% yield).
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([OH:34])=O)(=[O:28])=[O:27].Cl.[NH:39]1[CH2:44][CH2:43][C:42](=[O:45])[CH2:41][CH2:40]1.CCN(C(C)C)C(C)C>ClCCl>[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([N:39]1[CH2:44][CH2:43][C:42](=[O:45])[CH2:41][CH2:40]1)=[O:34])(=[O:27])=[O:28]
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: O=C1CCNCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cccc(C(=O)N2CCC(=O)CC2)c1
Temperature: 25 °C
Yield: 93 %

Procedure:
PyBrOP™ (17.3 g) was added to a stirred mixture of 3-methanesulphonyl benzoic acid (7.35 g), 4-piperidone hydrochloride (5 g) and Hunig's base (25 ml) in dichloromethane (250 ml) with stirring at RT. The mixture was stirred overnight then washed with saturated NaHCO3 solution (200 ml) and then with saturated brine (200 ml). The organic layer was evaporated and the resulting residue purified by column chromatography (silica, 1:1 ethyl acetate:dichloromethane) to give the product as a thick oil (9.6 g; MS: APCI+(M+H) 282).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:30]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:19][CH:18]=4)[N:11]3[N:10]=2)=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]3[N:30]=[C:12]4[CH:13]=[CH:14][CH:15]=[C:16]([C:17]5[CH:22]=[CH:21][C:20]([CH2:23][N:24]6[CH2:29][CH2:28][O:27][CH2:26][CH2:25]6)=[CH:19][CH:18]=5)[N:11]4[N:10]=3)=[CH:4][CH:3]=2)[CH2:34][CH2:33]1
Reactant: Clc1ccc(Nc2nc3cccc(-c4ccc(CN5CCOCC5)cc4)n3n2)cc1
Reactant: CN1CCNCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(Nc3nc4cccc(-c5ccc(CN6CCOCC6)cc5)n4n3)cc2)CC1
Temperature: 160 °C
Yield: 11 %

Procedure:
A suspension of N-(4-chlorophenyl)-5-(4-(morpholinomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (300 mg, 0.7 mmol), 1-methylpiperazine (356 mg, 3.6 mmol), tris(dibenzylideneacetone)dipalladium (0) (65 mg, 0.07 mmol), cesium carbonate (456 mg, 1.4 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (410 mg, 0.07 mmol) in 1,4-dioxane (2 mL) was irradiated by microwave heating to 160° C. for 20 min. The reaction mixture was diluted with EtOAc (300 mL), and filtered though celite. The filtrate was concentrated to give a black residue, which was purified by preparative thin layer chromatography (10% methanol in dichloromethane) to afford product (38.9 mg 11% yield). 1H NMR (400 MHz, CDCl3), δ: 7.96 (d, J=8 Hz, 2H), 7.52-7.42 (m, 6H), 6.92-6.87 (m, 3H), 6.68 (m, 1H), 3.79-3.72 (m, 4H), 3.59 (s, 2H), 3.18-3.12 (m, 4H), 2.6-2.55 (m 4H), 2.55-2.48 (m, 4H), 2.33 (s, 3H). LCMS (ESI) m/z: 484.1.
Reaction SMILES: CO.[OH-].[Na+].[CH3:5][CH:6]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][CH:8]=[O:9].[CH:15](=[O:18])[CH2:16][CH3:17]>C(O)(=O)C>[CH3:5][CH:6]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][CH:8]=[O:9].[CH3:17][C:16](=[CH:8][CH2:7][CH:6]([CH3:5])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:15]=[O:18]
Reactant: CCC=O
Agent: CC(CC=O)CC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C=O)=CCC(C)CC(C)(C)C
Reaction time: 1 h

Procedure:
128 g (4 moles) of methanol and 2 g (0.05 mole) of NaOH were initially taken under nitrogen in a reaction flask and were refluxed. A mixture of 142 g (1 mole) of 3,5,5-trimethylhexanal and 116 g (2 moles) of propionaldehyde was added dropwise to this solution in the course of 10 minutes. The resulting reaction mixture was kept at the boil for 1 hour (h) and then brought to pH 4-5 with an 80% strength aqueous acetic acid solution. After washing twice with water, the organic phase was separated off and worked up by fractional distillation. 32 g of unconverted 3,5,5-trimethylhexanal, as light ends, and 113 g of 2,5,7,7-tetramethyl-2-octenal (bp.=108°-111° C./14 mbar) were obtained, corresponding to a selectivity of 81%, based on trimethylhexanal; nD25 =1.4580.
Reaction SMILES: [C:1]([C:3](=[C:9]([O:11][CH2:12][CH3:13])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[C:1]([C:3](=[C:9]([O:11][CH2:12][CH3:13])[CH:10]=[CH:16][N:17]([CH3:19])[CH3:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=C(C)OCC
Reactant: COC(OC)N(C)C
Product: CCOC(=O)C(C#N)=C(C=CN(C)C)OCC
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 2-cyano-3-ethoxybut-2-enoate (194 g theory, 1.06 mol) and N,N-dimethylformamide dimethyl acetal (160 g, 1.325 mol) was stirred at 70° C. for 2 hours. The mixture was concentrated under high vacuum to provide crude ethyl 2-cyano-5-(dimethylamino)-3-ethoxypenta-2,4-dienoate. The residue was used directly without further purification.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3ccc(Oc4ccccc4)cc3c2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CN2CCc3[nH]c4ccc(Oc5ccccc5)cc4c3CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.1 %

Procedure:
To a solution of 3-benzoyl-9-phenoxy-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.10 g, 0.26 mmol) in tetrahydrofuran (5.0 mL) was added lithium aluminum hydride (0.10 g, 2.61 mmol). The resulted mixture was stirred at room temperature for 16 h. Water (0.10 mL), 15% sodium hydroxide solution (0.10 mL) and water (0.30 mL) were added sequentially. The mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (silica gel, 50% EtOAc/hexane with 1% Et3N) to afford 0.093 g (99%) of colorless solid as the desired product. 1H NMR (300 MHz, CDCl3) δ 7.77, 7.21-7.44, 7.12, 6.95-7.04, 6.87, 3.00-2.91, 2.89-2.83.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].Br[C:10]([CH3:18])([CH3:17])[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12].CS(C)=O>C(OCC)C>[CH2:7]([O:6][C:4](=[O:5])[CH:3]([N+:1]#[C-:2])[C:10]([CH3:18])([CH3:17])[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH3:8]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: C=CCOC(=O)C(C)(C)Br
Solvent: CCOCC
Solvent: CS(C)=O
Product: [C-]#[N+]C(C(=O)OCC)C(C)(C)C(=O)OCC=C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl isocyanoacetate (2.19 g, 19.4 mmol) and allyl 2-bromo-2-methylpropionate (4.40 g, 21.3 mmol) are dissolved in diethyl ether (50 mL) and methyl sulfoxide (50 mL) with stirring. In a separate flask sodium hydride (775 mg of 60% dispersion in mineral oil) is rinsed with hexane and suspended in diethyl ether (10 mL). The suspension is added dropwise to the stirring solution and an additional methyl sulfoxide (50 mL) is added to the mixture. The reaction is stirred for 2 hours at room temperature. The mixture is diluted with diethyl ether (250 mL) and washed several times with water. The organic phase is dried over sodium sulfate and evaporated to give 3-isocyano-2,2-dimethyl-succinic acid 1-allyl ester 4-ethyl ester.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][NH:12][OH:13])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(Cl)Cl>[CH2:6]([O:5][P:4]([CH2:9][CH2:10][CH2:11][N:12]([OH:13])[C:14](=[O:16])[CH3:15])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: CCOP(=O)(CCCNO)OCC
Solvent: ClCCl
Product: CCOP(=O)(CCCN(O)C(C)=O)OCC
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 112.4 %

Procedure:
2.8 g (0.013 mol) 3-(N-hydroxyamino)-propylphosphonic acid diethylester are dissolved in 30 ml methylene chloride and added drop by drop with cooling with ice to 2.65 g (0.026 mol) acetic anhydride. The reaction mixture is stirred for 30 minutes at 0-5° C. and for a further 1.5 hours at room temperature. After concentration under reduced pressure until a yellow oily radical is achieved, this oily residue is taken up in 15 ml methanol and 5 ml water, adjusted to pH 8 with 2 n NaOH and stirred for a further 1.5 hours at room temperature. Methanol is removed under reduced pressure and the resultant solution is adjusted to pH=5 with concentrated HCl. The yellow solution is extracted repeatedly with methylene chloride (1×30 ml, 2×10 ml in each case), the combined CH2Cl2 phases are dried over MGSO4 and the solvent is removed at room temperature under reduced pressure. 3.7 g of a yellow oil are obtained which are freed from adhering volatile substances in the entire diaphragm pump vacuum. 2.78 g yellow oil remain.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:40](=[O:41])[N:13]3[C:14]([C:24]([O:26][CH:27]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])=[C:15]([CH2:19][S:20][CH2:21][CH:22]=[CH2:23])[CH2:16][S:17](=O)[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)Cl.O>C(Cl)Cl>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:40](=[O:41])[N:13]3[C:14]([C:24]([O:26][CH:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:25])=[C:15]([CH2:19][S:20][CH2:21][CH:22]=[CH2:23])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Solvent: O
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: C=CCSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Yield: 87 %

Procedure:
To a solution of benzhydryl 7-(2-phenylacetamido)-3-allylthiomethyl-3-cephem-4-carboxylate-1-oxide (26 g) in methylene chloride (500 ml) was added dropwise phosphorus trichloride (20 ml) at 5° C. with stirring, and the stirring was continued for an hour. The mixture was poured into a mixture of methylene chloride (200 ml) and water (400 ml), followed by separating out the organic layer, which was washed twice with an aqueous solution of sodium chloride (200 ml) and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was pulverized with diisopropyl ether to give benzhydryl 7-(2-phenylacetamido)-3-allylthiomethyl-3-cephem-4-carboxylate (22 g).
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[N+:15]#[N:16].[Cl-].COC1C=CC(Cl)=CC=1N>Cl.COC1C=CC(Cl)=CC=1[N+]#N.COC1C=CC(Cl)=CC=1[N+]#N.[Cl-].[Cl-].Cl[Zn]Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[C:9]([NH:15][NH2:16])[CH:10]=1
Reactant: COc1ccc(Cl)cc1[N+]#N
Agent: COc1ccc(Cl)cc1N
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: COc1ccc(Cl)cc1NN
Temperature: 0 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
Tin(II)chloride dihydrate (SnCl2.2H2O, 121 g, 0.54 mol) was dissolved in 300 ml concentrated HCl at −72° C. Diazo Red RC (Azoic Diazo No. 10, C.I. 37120, Fast Red RC Salt, Aldrich Chemical Co., 50 g, 0.18 mole) was added in portions with vigorous mechanical stirring. After the addition was complete, the reaction was stirred at 0° C. for three hours. The tan solid was filtered and washed with concentrated HCl, then stirred for 30 minutes in a mixture of 500 ml of dichloromethane and 500 ml 2N NaOH. The organic layer was separated, dried over sodium sulfate, concentrated under vacuum, and the resulting oil crystallized from 100 ml of diethyl ether to yield (5-chloro-2-methoxyphenyl)hydrazine (26.4 g, 84%). 1H NMR (300 MHz, CDCl3) δ6.96 (1H, d, J=2.4 Hz), 6.70 (1H, dd, 8.4, 2.4 Hz), 6.65 (1H, d, J=8.4 Hz), 3.81 (3H, s).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[CH:9]=O)[C:2]#[CH:3].[NH2:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:16]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OC(N1CCC[C@H](NCC2C=C(C(C#N)C)C=CC=2OC)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:24]([O:23][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:15]([NH:14][CH2:9][C:8]2[CH:11]=[C:4]([CH2:1][C:2]#[CH:3])[CH:5]=[CH:6][C:7]=2[O:12][CH3:13])[C@@H:16]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Reactant: C#CCc1ccc(OC)c(C=O)c1
Agent: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Product: C#CCc1ccc(OC)c(CN[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)c1

Procedure:
This compound was prepared from Compound 77 and Compound 17 in the same manner of Compound 18.