Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)[NH:4][C:5]1[O:6][C:7]2[C:13]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[C:8]=2[N:9]=1.[OH-].[Na+]>O1CCOCC1.C(O)CO>[CH3:21][O:20][C:10]1[C:8]2[N:9]=[C:5]([NH2:4])[O:6][C:7]=2[C:13]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:12][CH:11]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(C3CCOCC3)c2o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: OCCO
Product: COc1ccc(C2CCOCC2)c2oc(N)nc12
Temperature: 100 °C
Yield: 74.1 %

Procedure:
To a stirred solution of 130 g (4.24 mmol) [4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-yl]-carbamic acid methyl ester in 90 ml dioxane and 30 ml ethylene glycol was added 90 ml of a 5 N aq. sodium hydroxide solution, and the mixture was heated at 100° C. for 16 h. After cooling to room temperature, the mixture was poured onto water and extracted four times with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated in vacuo. Flash chromatography (dichloromethane then 5/95 methanol/dichloromethane) afforded 0.78 g (74%) 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-ylamine as a brown solid. ES-MS m/e (%): 249 (M+H+, 100).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][NH:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(CC)CC)C>ClCCCl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][N:22]([C:25](=[O:27])[CH3:26])[CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2cc(Nc3ccnc4[nH]c5c(c34)CNCC5)ccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(=O)N1CCc2[nH]c3nccc(Nc4ccc5ccccc5c4)c3c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.9 %

Procedure:
Naphthalen-2-yl-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (79 mg, 0.25 mmol), acetic anhydride (25 μL, 0.25 mmol), and triethylamine (104 μL, 0.75 mmol) were dissolved in 1,2-dichloroethane (2 mL), and stirred for 30 min at room temperature. The reaction was quenched with H2O, and the resulting material was filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude material was purified via Biotage eluting with a gradient of 0 to 10% MeOH in DCM. Lyophilization of the purified product provided 60 (24 mg, 26% yield) as a tan powder. LC-MS (M+H=357, obsd.=357).
Reaction SMILES: N1C=C[CH:4]=[CH:3][C:2]=1[C:7]([C:9]1C=CC=CN=1)=O.CO.[CH3:17][C:18]([OH:20])=[O:19].C(Cl)Cl>>[C:18]([OH:20])(=[O:19])/[CH:17]=[CH:4]/[CH2:3][CH2:2][CH2:7][CH3:9]
Reactant: CC(=O)O
Reactant: O=C(c1ccccn1)c1ccccn1
Solvent: ClCCl
Solvent: CO
Product: CCCC/C=C/C(=O)O
Yield: 70 %

Procedure:
Prepared as above from 376.4 mg (0.86 mmol) of the (±)-pyridyl ketone and 790.6 mg (1.73 mmol) of the Wittig salt. Preparative HPLC with MeOH-AcOH-CH2Cl2 (4:1:95) gave in ~92% yield a mixture of Wittig product (E/Z=~96:4) from which 320.9 mg (70%) of (±)-(E)-heptenoic acid was isolated cleanly: mp 68-73° C.; 1H NMR (CDCl3) δ8.61 (br s, 1H), 8.49 (br s, 1H), 8.28 (s, 1H), 8.06 (d, J=8.1 Hz, 2H), 7.52 (br s, 1H), 7.46 (br d, J=8.0 Hz, 1H), 7.28 (d, 2H), 7.27 (buried, 1H), 6.21 (t, J=7.4 Hz, 1H), 4.04 (dt, J=13.3, 1.9 Hz, 1H), 3.69 (br s, 4H), 3.50 (m, 5H), 2.33 (dd, J=7.1, 6.7 Hz, 2H), 2.21 (ddd, J=7.2, 7.0, 6.7 Hz, 2H), 1.89-1.26 (m, 10H); FDMS 534 (M+1). Anal. (C30H35N3O6.0.25C2H4O2) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[C:4]([Br:12])[C:3]=1[OH:13].CC(C)([O-])C.[K+].[Cl:20][C:21]1[N:22]=[N:23][C:24](Cl)=[CH:25][C:26]=1[CH:27]([CH3:29])[CH3:28]>CN(C)C(=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[C:4]([Br:12])[C:3]=1[O:13][C:24]1[N:23]=[N:22][C:21]([Cl:20])=[C:26]([CH:27]([CH3:29])[CH3:28])[CH:25]=1
Reactant: OCCCc1cc(Br)c(O)c(Br)c1
Reactant: CC(C)c1cc(Cl)nnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)c1cc(Oc2c(Br)cc(CCCO)cc2Br)nnc1Cl
Temperature: 100 °C
Reaction time: 24 h
Yield: 24.7 %

Procedure:
A mixture of 2,6-dibromo-4-(3-hydroxy-propyl)-phenol (20) (5.0 g, 16.3 mmol) in N,N-dimethyl acetamide (8 mL) was treated with potassium tert-butoxide (1.74 g, 15.48 mmol) under nitrogen at room temperature. The suspension was heated to 100° C. for 15 min and turned brown in color. 3,6-Dichloro-4-isopropyl pyridazine (7) (2.47 g, 12.9 mmol) was added to the suspension and the reaction was stirred at 140° C. for 24 h. The reaction was cooled to room temperature, diluted with water (180 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were combined and were washed with a 1N aqueous sodium hydroxide solution (1×150 mL), followed by a saturated aqueous sodium chloride solution (1×150 mL). The organic layer was dried with sodium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography (Biotage 40M) eluted with 15% ethyl acetate in hexanes, followed by 25% ethyl acetate in hexanes, followed by 50% ethyl acetate in hexanes. The desired fractions were collected and concentrated under vacuum. The resulting solid was slurried in cold acetonitrile and filtered. The solid was then diluted with a 1:1 mixture of isopropyl acetate:methyl tert-butyl ether (20 mL). The mixture was heated to reflux and then cooled to room temperature. The solvent was decanted. The solid was slurried in heptane, filtered and dried under high vacuum overnight. The filtrate was concentrated. The resulting solid was then diluted with a 1:1 mixture of isopropyl acetate: methyl tert-butyl ether (20 mL). The mixture was heated to reflux and then cooled to room temperature. The solvent was decanted and the solid was slurried in heptane and filtered to afford a second crop of solid which was dried under high vacuum overnight. The solids were combined to afford 3-[3,5-dibromo-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-propan-1-ol (21) (1.48 g, 20%) as a white solid; LRMS for C16H17Br2ClN2O2 (M+H) m/z=465. Molecular Weight=464.5871; Exact Mass=461.9345
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[C:6]([CH2:22][CH3:23])([OH:21])[C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1.[H][H]>[Pd].CO>[F:1][C:2]([F:27])([F:28])[C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[C:6]([CH2:22][CH3:23])([OH:21])[C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: CCC(O)(c1ccc(OCc2ccccc2)cc1)c1cccc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC(O)(c1ccc(O)cc1)c1cccc(C(F)(F)F)c1

Procedure:
54.1 g. of 3-trifluoromethyl-4'-benzyloxy-α-ethyl-benzhydrol in 541 ml. of methanol are hydrogenated under atmospheric pressure, in the presence of 27.1 g. of a 10% palladium-on-charcoal catalyst. When the uptake of the calculated amount of hydrogen is complete, the catalyst is filtered off, and the solvent is distilled off under reduced pressure. The crude product is decoloured with charcoal in ethyl acetate, and recrystallized from a mixture of ethyl acetate and n-hexane. 30.8 g. of the named compound are obtained, melting at 102.5° to 103° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:23]=[CH:24][CH:25]=2)[O:17][CH2:18][C:19]([O:21]C)=O)=[O:10])[CH:2]=1.[CH3:26][NH2:27].CO>CO>[CH3:26][NH:27][C:19]([CH2:18][O:17][C:16]1[CH:15]=[C:14]([CH:25]=[CH:24][CH:23]=1)[CH2:13][CH2:12][NH:11][C:9](=[O:10])/[CH:8]=[CH:7]/[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:21]
Reactant: CN
Reactant: COC(=O)COc1cccc(CCNC(=O)/C=C/c2cccnc2)c1
Solvent: CO
Product: CNC(=O)COc1cccc(CCNC(=O)/C=C/c2cccnc2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 88 %

Procedure:
Methyl [3-[2-[(E)-3-(3-pyridyl)acryloylamino]-ethyl]phenoxy]acetate (0.34 g, 1.0 mmol) obtained in Example 94 was dissolved in methanol (6 ml) and 40% methylamine-methanol solution (0.8 ml) was added and stirred at room temperature for 17 hours. After concentrating the reaction mixture under reduced pressure, the residue was recrystallized to yield the titled compound (0.30 g, 88%).
Reaction SMILES: O.[NH2:2][CH2:3][CH:4]1[C:10]2=[CH:11][NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[C:8]([C:9]=32)[C:7](=[O:17])[NH:6][CH2:5]1.[CH3:18][C:19]([CH3:21])=O>O1CCCC1>[CH:19]([NH:2][CH2:3][CH:4]1[C:10]2=[CH:11][NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[C:8]([C:9]=32)[C:7](=[O:17])[NH:6][CH2:5]1)([CH3:21])[CH3:18]
Reactant: CC(C)=O
Reactant: NCC1CNC(=O)c2cccc3[nH]cc1c23
Solvent: O
Solvent: C1CCOC1
Product: CC(C)NCC1CNC(=O)c2cccc3[nH]cc1c23
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
0.82 g of borane-dimethylamine complex was added to a stirred solution of 3-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole hydrate (see Example 1C for preparation) in 80 ml of tetrahydrofuran. The solution was heated under reflux for 1 hour and subsequently, at a temperature of 45° C., 10 ml of acetone were added dropwise. The reaction mixture was stirred at a temperature of 60° C. for 2.5 hours. To work up the reaction mixture it was subsequently evaporated to dryness, and the residue was dissolved in a mixture of water and dichloromethane. The dichloromethane phase was separated, and the aqueous phase was extracted three more times with 50 ml portions of a 9:1 dichloromethane/methanol mixture. The organic phases were combined and evaporated to dryness. The crude product which remained as residue was purified by chromatography under slightly elevated pressure (=flash chromatography) on silica gel using methanol/ethyl acetate 4:1 as eluent. The title compound was obtained as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])[CH:6]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: COC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (3-hydroxy-phenyl)-acetic acid methyl ester (4.26 g, 25.66 mmol) and potassium carbonate (7.1 g, 51.33 mmol) in DMF (60 mL) is added 4-chloromethyl-5-methyl-2-phenyl-oxazole (5.33 g, 25.66 mmol) at RT. The reaction mixture is stirred for 16 h at 40° C. followed by 16 h at 60° C. The reaction mixture is cooled to RT, diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated at reduced pressure. The crude product is purified on a Biotage 40M column using 25% ethyl acetate in hexane to yield [3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-acetic acid methyl ester as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.O.[NH2:23][NH2:24].O>N1C=CC=CC=1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:6]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[CH:5][N:4]=[N:3][C:2]=2[NH:23][NH2:24])=[CH:9][CH:10]=1
Reactant: Clc1ccc(-c2cnnc(Cl)c2-c2ccc(Cl)cc2)cc1
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: NNc1nncc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Yield: 96 %

Procedure:
3-Chloro-4,5-bis(4-chlorophenyl)pyridazine (10.0 g, 30.0 mmol) was dissolved in pyridine (30 mL) and hydrazine mono-hydrate was added (4.5 g, 90.0 mmol). The reaction mixture was refluxed for 3 h and was then added to water (100 mL). The pale colored solid was collected by filtration and rinsed thoroughly with water. The product was dried in a vacuum oven to give the title compound, 1-(4,5-bis(4-chlorophenyl)pyridazin-3-yl)hydrazine (9.5 g, 96%). MS: M+H=331. 1H NMR (DMSO-d6, 500 MHz): δ 8.59(1H, s), 8.56 (1H, br), 7.40 (2H, d, J=10 Hz), 7.35 (2H, d, J=10.0 Hz), 7.14–7.16 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].Cl>C1COCC1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[C:4]([F:9])[CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred, cooled (0° C.) solution of 3.64 g (25.0 mmol) of 4-chloro-2-fluoroaniline and 4.2 mL (30 mmol) of triethylamine in 50 mL of THF was added 4.18 mL (26 mmol) of pivaloyl chloride. After stirring for 10 min. at 0° C. the mixture was warmed to ambient temperature and poured into 0.5N HCl. The mixture was extracted with 100 mL of ether, and the organic extract was washed sequentially with NaHCO3 and brine. The solution was dried (MgSO4), concentrated under reduced pressure, and chromatographed on silica gel (elution with 3:1 hexanes-ether) to give, after removal of solvent, 5.2 g (92%) of 4′-chloro-2′-fluoro-2,2-dimethylpropionanilide as a pale pink solid (IX), mp 70.5-71° C. 1H NMR (300 MHz, CDCl3) δ8.36(t, 1H, J=8.4 Hz); 7.57(br. s, 1H); 7.10-7.17(m, 2H); 1.30(s, 9H). 19F NMR (282 MHz, CDCl3) δ−129.8. High resolution mass spec: calculated for C11H14NOClF(M+H)+: 230.0748, found: 230.0760.
Reaction SMILES: Cl[C:2]1C2OCCCC=2C(C)=C(C2C(C3SC=CC=3)=NN(C)C=2C=O)C=1.[Cl:26][C:27]1[C:36]2[O:35][CH2:34][CH2:33][CH2:32][C:31]=2[C:30]([CH3:37])=[C:29]([C:38]2[C:39]([C:49]3[S:50][CH:51]=[CH:52][CH:53]=3)=[N:40][N:41]([CH3:48])[C:42]=2[CH:43]([OH:47])[C:44]([O-:46])=[O:45])[CH:28]=1>C1CCCCC1.C(OCC)(=O)C>[Cl:26][C:27]1[C:36]2[O:35][CH2:34][CH2:33][CH2:32][C:31]=2[C:30]([CH3:37])=[C:29]([C:38]2[C:39]([C:49]3[S:50][CH:51]=[CH:52][CH:53]=3)=[N:40][N:41]([CH3:48])[C:42]=2[CH:43]([OH:47])[C:44]([O:46][CH3:2])=[O:45])[CH:28]=1
Reactant: Cc1c(-c2c(-c3cccs3)nn(C)c2C(O)C(=O)[O-])cc(Cl)c2c1CCCO2
Reactant: Cc1c(-c2c(-c3cccs3)nn(C)c2C=O)cc(Cl)c2c1CCCO2
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: COC(=O)C(O)c1c(-c2cc(Cl)c3c(c2C)CCCO3)c(-c2cccs2)nn1C

Procedure:
Using the procedure described in example 1, step 5, 4-(8-chloro-5-methyl-3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-3-(thiophen-2-yl)-1H-pyrazole-5-carbaldehyde (35a) (180 mg, 0.48 mmol) is converted, after purification by preparative TLC (dichloromethane/ethyl acetate 70/30) into 2-[4-(8-chloro-5-methyl-3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-3-(thiophen-2-yl)-1H-pyrazol-5-yl]-2-hydroxyacetate (35b) (69 mg, 0.16 mmol, 33%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH2:36](Br)[CH:37]=[CH2:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:38][CH:37]=[CH2:36])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2
Reactant: C=CCBr
Product: C=CCOc1cc2c(cc1OC)CCN(CC(=O)NCc1ccccc1)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with allyl bromide
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:7]([C:13]#[N:14])=[N:8][CH:9]=[C:10]([Br:12])[CH:11]=1.[ClH:15]>O.[Cu]>[Br:12][C:10]1[CH:11]=[C:6]([Cl:15])[C:7]([C:13]#[N:14])=[N:8][CH:9]=1
Reactant: N#Cc1ncc(Br)cc1N
Reactant: Cl
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ncc(Br)cc1Cl
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
Sodium nitrite (0.7 g, 10.15 mmol) was added to a cooled suspension of 3-amino-5-bromopicolinonitrile (1.67 g, 8.43 g) in 37% hydrochloric acid (14 ml, 169 mmol) and water (4.5 ml) and stirred for 1 h at 0-5° C. Copper powder (0.134 g, 2.11 mmol) was added and the mixture refluxed for 1 h. The mixture was cooled, quenched with ice water and basified with 48% NaOH. The mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated to give 1.21 g of the product. 1H-NMR (400 MHz; d6-DMSO): δ 8.75 (d, 1H, J=1.9 Hz), 8.90 (d, 1H, J=1.9 Hz).
Reaction SMILES: O[C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C([O-])(O)=O.[Na+].O>[CH:16]1([C:13]2[CH:12]=[CH:11][C:10]([C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CCOC(=O)CC(C)(O)c1ccc(C2CCCCCCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C=C(C)c1ccc(C2CCCCCCC2)cc1
Yield: 81 %

Procedure:
To a solution of ethyl 3-hydroxy-3-(4′-cyclooctylphenyl)-butanoate (2d, 36 g) in benzene (350 ml) was added p-toluenesulfonic acid and refluxed for 2.5 h. The mixture was diluted with saturated NaHCO3 solution (20 ml) and water (50 ml) and benzene layer was separated out. Aqueous layer was extracted with benzene (2×200 ml) combined organic layer was washed with water (2×20 ml), dried over Na2SO4 and concentrated. Crude product was purified by column chromatography to furnish 27.5 g (81.1% yield) of ethyl 3-(4′-cyclooctylphenyl)-but-2-enoate (3d, formula 3, R=cyclooctyl) as oil.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10]1)C)(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[NH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[C:16]1[C:14]([N:11]1[CH2:12][CH2:13][CH:9]([NH:7][CH3:6])[CH2:10]1)=[O:15]
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(C(=O)c2cc3ccccc3[nH]2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CCN(C(=O)c2cc3ccccc3[nH]2)C1
Reaction time: 18 h
Yield: 99 %

Procedure:
A solution of [1-(1H-indole-2-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (0.500 g, 1.46 mmol) in CH2Cl2 (20 mL) was treated with TFA (8 mL). After 18 h at rt, the mixture was concentrated to give the title compound (520 mg, 99%). MS (ESI): mass calcd. for C16H17N3O, 243.14; m/z found, 244.4 [M+H]+. MS (ESI): mass calcd. for C14H16N3O, 243.43; m/z found, 244.3 [M+H]+. 1H NMR (MeOD): 7.68-7.63 (m, 1H), 7.48-7.43 (m, 1H), 7.28-7.21 (m, 1H), 7.11-7.05 (m, 1H), 7.05-7.00 (m, 1H), 4.44-3.76 (m, 5H), 2.85-2.74 (m, 3H), 2.67-2.08 (m, 2H).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11](=[O:18])[NH:12]2.[C:19]([O-:22])(=[O:21])[CH3:20].[Na+].O>CN(C)C=O>[C:19]([O:22][CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11](=[O:18])[NH:12]2)(=[O:21])[CH3:20]
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(OC/C=C/CCl)c2ccc(=O)[nH]c12
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC/C=C/COc1ccc(C)c2[nH]c(=O)ccc12
Temperature: 120 °C
Reaction time: 6 h
Yield: 67.1 %

Procedure:
5-[(E-4-Chloro-2-butenyl)oxy]-8-methylcarbostyril (16.15 g) was dissolved in dimethylformamide (200 ml), to which sodium acetate (35.0 g) was added and stirred at 120° C. for 6 hours. After the reaction was completed, the reaction mixture was condensed under reduced pressure. Water was added to the condensate and extracted with chloroform. The chloroform phase was dried, and the solvent was removed. The residue was recrystallized from a solvent mixture of chloroform-ether to obtain 11.80 g of 5-[(E-4-acetoxy-2butenyl)oxy]-8-methylcarbostyril as colorless powdery crystals (67.1%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C@H:9]([C@@H:16]([OH:67])[C:17]([O:19][C@@H:20]1[C:50]([CH3:51])=[C:49]2[C:52]([CH3:54])([CH3:53])[C@:22]([OH:66])([C@@H:23]([O:57][C:58]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[O:59])[C@@H:24]3[C@:29]4([O:32][C:33]([CH3:35])=[O:34])[CH2:30][O:31][C@@H:28]4[CH2:27][C@H:26]([O:36][C@@H]4OC[C@@H](O)[C@H](O)[C@H]4O)[C@@:25]3([CH3:56])[C:46]([C@@H:48]2[OH:55])=[O:47])[CH2:21]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].I([O-])(=O)(=O)=O.[Na+]>C(O)C.O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C@H:9]([C@@H:16]([OH:67])[C:17]([O:19][C@@H:20]1[C:50]([CH3:51])=[C:49]2[C:52]([CH3:54])([CH3:53])[C@:22]([OH:66])([C@@H:23]([O:57][C:58]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[O:59])[C@@H:24]3[C@:29]4([O:32][C:33]([CH3:35])=[O:34])[CH2:30][O:31][C@@H:28]4[CH2:27][C@H:26]([OH:36])[C@@:25]3([CH3:56])[C:46]([C@@H:48]2[OH:55])=[O:47])[CH2:21]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: CCCCCC(=O)N[C@@H](c1ccccc1)[C@@H](O)C(=O)O[C@H]1C[C@@]2(O)[C@@H](OC(=O)c3ccccc3)[C@@H]3[C@]4(OC(C)=O)CO[C@@H]4C[C@H](O[C@@H]4OC[C@@H](O)[C@H](O)[C@H]4O)[C@@]3(C)C(=O)[C@H](O)C(=C1C)C2(C)C
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCO
Solvent: O
Product: CCCCCC(=O)N[C@@H](c1ccccc1)[C@@H](O)C(=O)O[C@H]1C[C@@]2(O)[C@@H](OC(=O)c3ccccc3)[C@@H]3[C@]4(OC(C)=O)CO[C@@H]4C[C@H](O)[C@@]3(C)C(=O)[C@H](O)C(=C1C)C2(C)C
Temperature: 30 °C
Reaction time: 30 h

Procedure:
To a small reaction flask was added the analogue 7-xylosyl-10-deacetyl taxol C (200 mg) in ethanol (300 ml); Sodium periodate (450 mg in 4 ml water) was added to the resulting solution and the reaction mixture was stirred for 20-40 hours at 20-40° C. The reaction mixture was diluted with water and extracted with ethyl acetate (2×50 ml). The ethyl acetate phase was washed with water, dried over anhydrous sodium sulphate and concentrated in vacuo to a residue. The residue was dissolved in a mixture of methanol--acetic acid and was treated with diethyl hydrozine sulphate (500 mg) for 12-18 hours at 0-40° C. with stirring. The reaction mixture was diluted with water and extracted with chloroform (2×50 ml). The chloroform layer was washed with water (2×50 ml), dried over anhydrous sodium sulphate and concentrated in vacuo to give a residue of 10-DAT, C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=1)([O-:3])=[O:2].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cn1
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc([N+](=O)[O-])cn1)N1CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 155.4 %

Procedure:
To a solution of 5-nitropicolinic acid (CIII) (500 mg, 2.97 mmol) in DMF (15 mL) was added pyrrolidine (244 μl, 2.47 mmol) and DIPEA (1.03 mL, 5.95 mmol). The reaction was cooled at 0° C. before adding HATU (1.13 g, 2.47 mmol). The reaction was warmed to room temperature and stirred for 2 hrs. The reaction was concentrated under vacuum and then dissolved in a mixture of water and 10% iPrOH/CHCl3. The organic layer was separated and the aqueous phase was washed again with 10% iPrOH/CHCl3. The combined organic phases were washed with brine, dried over MgSO4 and evaporated to yield (5-nitropyridin-2-yl)(pyrrolidin-1-yl)methanone (CIV) as a red solid (849 mg). ESIMS found for C10H11N3O3 m/z 222.1 (M+H).