Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[CH2:6][N:7]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:15]=3)[C:10]([OH:25])=[C:9]([C:26]([O:28]CC)=O)[C:8]2=[O:31])[CH2:3][CH2:2]1.[CH:33]1([NH2:37])[CH2:36][CH2:35][CH2:34]1>>[CH:33]1([NH:37][C:26]([C:9]2[C:8](=[O:31])[N:7]([CH2:6][C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[O:32])[C:16]3[C:11]([C:10]=2[OH:25])=[N:12][CH:13]=[C:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:15]=3)=[O:28])[CH2:36][CH2:35][CH2:34]1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)NC2CC2)c1=O
Reactant: NC1CCC1
Product: O=C(Cn1c(=O)c(C(=O)NC2CCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21)NC1CC1

Procedure:
This compound was prepared from ethyl 1-[2-(cyclopropylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclobutylamine by methods similar to those described in Example 245. The crude material was triturated with a mixture of MeOH and 1N HCl to afford the product as a white solid: 1H NMR (d6-DMSO) δ 10.30 (1H, d, J=7 Hz), 8.54 (1H, s), 8.24 (1H, d, J=4 Hz), 7.74 (1H, s), 7.32 (2H, dd, J=8.4, 5.7 Hz), 7.11 (2H, t, J˜9 Hz), 4.80 (2H, s), 4.40 (1H, m, J=8 Hz), 4.11 (2H, s), 2.56 (1H, m), 2.29 (2H, m), 2.03 (2H, m), 1.71 (2H, m), 0.59 (2H, m), 0.36 (2H, m); HRMS calcd for C25H25FN4O4+H+: 465.1938. Found: 465.1934.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([N:6]3[C:11]([CH2:12][O:13]2)=[N:10][NH:9][C:8](=[O:16])[C@H:7]3[CH3:17])=[CH:4][C:3]=1[NH:18][C:19]1([CH3:24])[CH2:22][N:21]([CH3:23])[CH2:20]1.[CH2:25]([O:27]/[CH:28]=[CH:29]/B1OC(C)(C)C(C)(C)O1)[CH3:26].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:23][N:21]1[CH2:22][C:19]([NH:18][C:3]2[CH:4]=[C:5]3[C:14](=[CH:15][C:2]=2/[CH:26]=[CH:25]/[O:27][CH2:28][CH3:29])[O:13][CH2:12][C:11]2[N:6]3[C@H:7]([CH3:17])[C:8](=[O:16])[NH:9][N:10]=2)([CH3:24])[CH2:20]1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(Br)c(NC4(C)CN(C)C4)cc3N21
Reactant: CCO/C=C/B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CCO/C=C/c1cc2c(cc1NC1(C)CN(C)C1)N1C(=NNC(=O)[C@H]1C)CO2
Temperature: 100 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
To a solution of (R)-7-bromo-6-(1,3-dimethyl-azetidin-3-ylamino)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (1.2 g, 3.04 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.66 g, 3.35 mmol) in a mixture of dioxane (12 mL) and water (2 mL) was added PdCl2(dppf)-CH2Cl2 adduct (0.25 g, 0.30 mmol) and K2CO3 (0.842 g, 6.09 mmol). The mixture was stirred at 100° C. for 3 h. The mixture was cooled to ambient temperature and the solvent was removed in vacuo to give the residue product, which was purified by chromatography on silica gel (eluting with 10% MeOH in dichloromethane) to give (R)-6-(1,3-dimethyl-azetidin-3-ylamino)-7-((E)-2-ethoxy-vinyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.8 g, 68%) 1H NMR (400 MHz, CDCl3) δ=8.20 (s, 1H), 6.80 (s, 1H), 6.71 (d, J=12.4 Hz, 1H), 5.90 (s, 1H), 5.64 (d, J=12.4 Hz, 1H), 4.63-4.46 (m, 3H), 3.91 (q, J=6.8 Hz, 2H), 3.53 (m, 2H), 3.27 (m, 2H), 2.43 (s, 3H), 1.61 (s, 3H), 1.50 (d, J=6.8 Hz, 3H), 1.35 (t, J=6.8 Hz, 3H). LC/MS (Table 1, Method 2) Rt=0.889 min; MS m/z: 386 [M+H]+.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.FC(F)(F)C(O)=O.[NH:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)(=[O:35])=[O:34])[CH2:21][CH2:20]1>>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:19]3[CH2:24][CH2:23][CH:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[NH:32][S:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)(=[O:35])=[O:34])[CH2:21][CH2:20]3)[O:3][C:4]=2[CH:10]=1
Reactant: Clc1ccc2nc(Cl)oc2c1
Reactant: O=S(=O)(Nc1ccccc1OC1CCNCC1)c1ccccn1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccccc1OC1CCN(c2nc3ccc(Cl)cc3o2)CC1)c1ccccn1

Procedure:
Compound 22 is prepared using synthesis method 3 using intermediates 2f and 6a (yield: 83%).
Reaction SMILES: Cl.Cl[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1.[CH2:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:11][CH3:12]>ClCCl>[CH2:10]([N:13]([CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1)[CH2:14][CH2:15][CH3:16])[CH2:11][CH3:12]
Reactant: ClCC1CCCCN1
Reactant: CCCNCCC
Agent: Cl
Solvent: ClCCl
Product: CCCN(CCC)CC1CCCCN1

Procedure:
A mixture of 170.1 g (1.0 mole) of 2-(chloromethyl)piperidine hydrochloride (M. Rink and H. G. Liem, Arch. Pharm. 292, 165-169 (1959)), 506 g (5.0 mole) of dipropylamine and 1.7 1 of dichloromethane were boiled under reflux for 3 hours, then evaporated in vacuo, and the residue was made alkaline with potassium hydroxide solution with external ice cooling. Exhaustive extraction with t-butyl methyl ether was carried out, and the combined extracts were washed twice with 100 ml of water each time, dried over sodium sulphate, and the solvent was removed by distillation in vacuo. The residue was fractionally distilled under water pump vacuum. Colourless oil of boiling point 108-114° C. (12 mm Hg ). Yield: 108.6 g (55% of theory).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]3[CH:23]=[C:22]([NH2:24])[N:21]=[C:20]([NH2:25])[N:19]=3)[CH:12]=2)=[CH:5][CH:4]=1.[Cl:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([N+:38]([O-:40])=[O:39])[CH:36]=2)[N:31]=[CH:30][CH:29]=1.Cl.CO.CCOC(C)=O>CCO.O.CCOC(C)=O>[ClH:27].[ClH:1].[NH2:25][C:20]1[N:19]=[C:18]([NH:17][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([NH:2][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([N+:38]([O-:40])=[O:39])[CH:36]=4)[N:31]=[CH:30][CH:29]=3)=[CH:4][CH:5]=2)=[O:26])[CH:23]=[C:22]([NH2:24])[N:21]=1
Reactant: Nc1ccc(NC(=O)c2cccc(Nc3cc(N)nc(N)n3)c2)cc1
Reactant: O=[N+]([O-])c1ccc2nccc(Cl)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Nc1cc(Nc2cccc(C(=O)Nc3ccc(Nc4ccnc5ccc([N+](=O)[O-])cc45)cc3)c2)nc(N)n1
Temperature: 20 °C

Procedure:
To a solution of amine B6 (204 mg, 0.55 mmol) in EtOH (20 mL) and H2O (10 mL) was added 4-chloro-6-nitroquinoline (126 mg, 0.61 mmol) and stirred until it dissolved, then 2 drops of c.HCl was added. The reaction mixture was refluxed for 4 h, diluted with EtOAc, brought to boil and cool to 20° C. The resulting precipitate was filtered and recrystallized from MeOH/EtOAc to give Cpd. RRR1 (224 mg 70%); m.p. (MeOH/EtOAc)>300° C.; 1H NMR [(CD3)2SO] δ 14.75 (br, 1 H, N+H), 11.50 (br, 1 H, N+H), 11.10 (br, 1 H, NH), 10.50 (s, 1 H, NH), 9.88 (s, 1 H, NH), 9.77 (s, 1 H, NH), 9.76 (s, 1 H, ArH), 8.66 (d, J=9.3 Hz, 1 H, ArH), 8.60 (d, J=6.8 Hz, 1 H, ArH), 8.19 (d, J=9.3 Hz, 1 H, ArH), 8.25 (d, J=8.8 Hz, 2 H, ArH), 7.94 (br s 2 H, NH2), 7.71 (d, J=7.6 Hz, 1 H, ArH), 7.56-7.42 (m, 6 H, NH2 & 4×ArH), 6.91 (d, J=6.8 Hz, 1 H, ArH), 5.44 (s, 1 H, ArH). HRMS (FAB+) calc. for C26H22N9O3 (M+1) m/z 508.1846, found 508.1841.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]3)[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH:22]([N:19]1[CH2:20][CH2:21][CH:16]([O:15][C:12]2[CH:13]=[CH:14][C:8]3[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[S:10][C:9]=3[CH:11]=2)[CH2:17][CH2:18]1)([CH3:24])[CH3:23]
Reactant: CCOC(=O)c1cc2ccc(OC3CCN(C(C)C)CC3)cc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)N1CCC(Oc2ccc3cc(C(=O)O)sc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 144 %

Procedure:
The above prepared 6-(1-isopropyl-piperidin-4-yloxy)-benzo[b]thiophene-2-carboxylic acid ethyl ester (0.359 g, 1.033 mmol) was dissolved in 2 mL of THF/ethanol=1/1 and treated with 0.517 mL of aq. NaOH (3M, 1.5 eq.). The mixture was stirred for 1 h at ambient temperature and was then neutralized by adding 0.77 mL of 2M HCl (1.5 eq.). Careful evaporation of all solvents and drying afforded then 0.475 g of the title compound as white solid contaminated with innocouos inorganic salts.
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15](Br)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:28]4[CH:27]=[CH:26][C:25]([O:24][C:23]([F:22])([F:34])[F:35])=[CH:30][CH:29]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(Br)ccc32)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(Cn2ccc3cc(-c4ccc(OC(F)(F)F)cc4)ccc32)cc1

Procedure:
1-[4-(tert-Butyl)benzyl]-5-[4-(trifluoromethoxy)phenyl]-1H-indole was prepared by coupling 1-[4-(tert-Butyl)benzyl]-5-bromo-1H-indole (5.34 g, 15.6 mmol), and 4-trifluoromethoxyphenyl boronic acid (3.86 g, 18.7 mmol), using [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.453 g, 0.555 mmol), and potassium carbonate (3.22 g, 23.3 mmol) in dioxane (120 mL) and water (11.8 mL) following the procedure described in Step 1 of Example 11. Purification by flash chromatography (Biotage apparatus) using hexane as the mobile phase yielded a dark yellow gum that solidified upon standing to a light yellow solid (2.53 g, 38%). 1HNMR (300 MHz, DMSO-d6): δ 7.95 (s, 1H), 7.75 (d, 2H, J=7.7 Hz), 7.55-7.6 (m, 2H), 7.45 (d, 3H, J=7.7 Hz), 7.35 (d, 2H, J=7.7 Hz), 7.15 (d, 2H, J=7.7 Hz), 6.45 (d, 1H, J=3.9 Hz), 5.4 (s, 2H), and 1.2 ppm (s, 9H).
Reaction SMILES: [CH:1](=[C:3]1[CH2:20][C@@:19]2([CH3:21])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[O:22][CH3:23])[CH2:5][C:4]1=[O:24])[CH3:2]>[Pd]>[CH2:1]([C@H:3]1[CH2:20][C@@:19]2([CH3:21])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[O:22][CH3:23])[CH2:5][C:4]1=[O:24])[CH3:2]
Reactant: CC=C1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC)CC[C@@H]32)CC1=O
Agent: [Pd]
Product: CC[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC)CC[C@@H]32)CC1=O

Procedure:
Palladium on charcoal (5%, 110 mg.) is added to a solution of 2-ethylidene-17β-methoxy-5α-androstan-3-one (Preparation 1, 1.5 g.) and shaken under hydrogen. The catalyst is removed by filtration and the filtrate is concentrated to dryness and chromatographed to give 2β-ethyl-17β-methoxy-5α-androstan-3-one.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[NH:15])[CH2:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[F:14])[CH3:3].[C:16](N)(=O)C(NN)=O.CN>CN(C)C=O>[CH2:2]([O:4][C:5](=[N:15][CH3:16])[CH2:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[F:14])[CH3:3]
Reactant: CCOC(=N)Cc1c(F)cccc1F
Reactant: NNC(=O)C(N)=O
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(Cc1c(F)cccc1F)=NC
Reaction time: 1 h

Procedure:
70.7 g (300 mmol) of 1-ethoxy-2-(2,6-difluorophenyl)-1-imino-ethane hydrochloride are added, while stirring, to a suspension of 30.9 g (300 mmol) of oxalic acid monoamide monohydrazide in 900 ml of N,N-dimethylformamide. The reaction mixture is heated to 80° and stirred at this temperature for 1 hour. During a period of 20 minutes 10.6 g of methylamine are passed into the resulting white suspension, which leads to the formation of a clear yellow solution. During a period of 1 hour a further 15.9 g of methylamine are passed into the solution. The solution is then stirred for another hour at 80°. The solvent is evaporated in vacuo. 400 ml of water are added to the residue. The aqueous mixture is stirred and the crystals are filtered off. 300 ml of water are added to the crystals. The mixture is again stirred and the crystals are filtered off. The crystals are dissolved in hot ethanol (ca. 500 ml). After the addition of activated charcoal the mixture is filtered over Hyflo. The filtrate is evaporated until crystallisation starts (ca. 230 ml of ethanol have to be distilled off). The mixture is then cooled in an ice bath. The crystals are filtered off and dried overnight in vacuo, yielding the product of example 1.
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][CH:41]3[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34]([OH:36])=O)[CH2:28][CH2:27]1.CS(N)(=O)=O.[N:54]1([S:58]([NH2:61])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55]1>>[N:54]1([S:58]([NH:61][C:34](=[O:36])[C:33]2[CH:37]=[C:29]([CH:26]3[CH2:27][CH2:28]3)[C:30]([O:39][CH2:40][CH:41]3[CH2:46][CH2:45][C:44]([F:47])([F:48])[CH2:43][CH2:42]3)=[CH:31][C:32]=2[F:38])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CCC(F)(F)CC2)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in preparation of Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)-benzoic acid with 5-cyclopropyl-4-((4,4-difluorocyclohexyl)-methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained (0.14 g, 47%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.72-8.57 (m, 1H), 7.66-7.54 (m, 1H), 6.64-6.50 (m, 1H), 4.32-4.19 (m, 4H), 3.96-3.83 (m, 2H), 2.35-2.09 (m, 4H), 2.09-1.68 (m, 6H), 1.62-1.41 (m, 2H), 1.04-0.87 (m, 2H), 0.76-0.62 (m, 2H); MS (ES+) m/z 447.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:21])[C:19]=1[Cl:20])[NH2:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:14]=[C:13]([Cl:12])[C:19]([Cl:20])=[C:18]([Cl:21])[CH:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1
Product: O=C(Nc1cc(Cl)c(Cl)c(Cl)c1)c1cc(Br)ccc1O
Yield: 78.6 %

Procedure:
Using 5-bromosalicylic acid and 3,4,5-trichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1)=[O:3].[C:11](Cl)(=[O:18])[CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[C:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:18])[CH2:12][CH2:13][CH2:14][C:15]([NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:2](=[O:3])[CH3:1])[CH:5]=2)=[O:16])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1cccc(N)c1
Reactant: O=C(Cl)CCCC(=O)Cl
Product: CC(=O)c1cccc(NC(=O)CCCC(=O)Nc2cccc(C(C)=O)c2)c1

Procedure:
N,N'-bis(3,5-diacetylphenyl)(isophthalic acid diamide), mp 283°-4° C. Also analogously, N,N'-bis(3-acetylphenyl)pentanediamide, mp 174°-5° C. was prepared from 3-aminoacetophenone and glutaryl dichloride.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)[Cl:15]>>[Cl:15][CH2:14][CH:16]([OH:18])[CH2:17][N:11]1[CH2:12][CH2:13][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1
Reactant: ClCC1CO1
Reactant: c1ccc(CC2CCNCC2)cc1
Product: OC(CCl)CN1CCC(Cc2ccccc2)CC1
Yield: 100 %

Procedure:
Treatment of amine 6 with epichlorohydrin, following the procedure described in Example 12, Step 1, gave crude 1-chloro-3-(4-benzylpiperidin-1-yl)propan-2-ol (29.03 g, >100%) as a clear, colorless oil:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[O:13][CH2:12][CH2:11][O:10]1.C([Li])CCC.CN(C)[CH:21]=[O:22].O>O1CCCC1.CCCCCC>[Cl:1][C:2]1[C:3]([CH:9]2[O:10][CH2:11][CH2:12][O:13]2)=[CH:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: Clc1ccc(C2OCCO2)c(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: O=Cc1c(Cl)ccc(C2OCCO2)c1Cl
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2,4-dichlorophenyl)-1,3-dioxolane (31.9 g) in tetrahydrofuran (220 ml) was added dropwise 1.6M n-butyllithium in hexane (110 ml) at -60 to -50° C. in a dry ice-acetone bath, and the mixture was stirred at -50° C. After 1 hour, to the reaction mixture was added N,N-dimethylformamide (56.4 ml). After 15 minutes, the mixture was stirred at ambient temperature for 1 hour then water (200 ml) was added thereto. The mixture was extracted with ethyl acetate (100 ml) twice, the organic layer was washed with water 3 times, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash silica gel chromatography eluted with n-hexane-ethyl acetate (10:1, V/V) and crystallized with diisopropyl ether to give 2,6-dichloro-3-(1,3-dioxolan-2-yl)benzaldehyde (4.91 g) as colorless crystals.
Reaction SMILES: C(O)(=O)C.[C:5]([C:8]1[CH:32]=[CH:31][C:11]([O:12][CH:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([O:28][CH2:29][CH3:30])[CH:19]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=1)(=[NH:7])[NH2:6].C([O-])(O)=O.[Na+].Cl[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40]>C(Cl)Cl>[CH2:42]([O:41][C:39]([NH:7][C:5]([C:8]1[CH:9]=[CH:10][C:11]([O:12][CH:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([O:28][CH2:29][CH3:30])[CH:19]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:31][CH:32]=1)=[NH:6])=[O:40])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOc1cc(C(Oc2ccc(C(=N)N)cc2)C(=O)OC)ccc1OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOc1cc(C(Oc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)C(=O)OC)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a suspension of 9C (570 mg, 1.12 mmol) in CH2Cl2 (12 mL) was added 1.0 M NaHCO3 (11.2 mL, 11.2 mmol), followed by benzyl chloroformate (0.22 mL, 1.5 mmol) in CH2Cl2 (3.0 mL). The mixture was stirred at rt for 30 min. TLC indicated some 9C still present. Another portion of benzyl chloroformate (0.1 mL, 0.84 mmol) in CH2Cl2 (3.0 mL) was added. After stirring at rt for 1.0 h, the reaction was quenched with ammonium hydroxide (0.65 mL), and extracted with CH2Cl2. The organic extract was washed with brine and dried over Na2SO4. After removal of the solvent, the crude product was purified by flash column chromatography eluting with ethyl acetate/hexanes (1:1) to give 9D (570 mg, 73% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.32 (d, J=6.16 Hz, 6H) 1.38 (t, J=7.03 Hz, 3H) 3.71 (s, 3H) 4.04 (q, J=7.03 Hz, 2H) 4.46 (m, 1H) 5.18 (s, 2H) 5.58 (s, 1H) 6.85 (d, J=8.8 Hz, 1H) 6.90 (d, J=8.35 Hz, 2H) 7.09 (m, 2H) 7.20-7.40 (m, 6H), 7.82 (d, J=9.20 Hz, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[N:36]=[C:37]([C@@H:40]6[CH2:44][CH2:43][CH2:42][N:41]6[C:45](=[O:55])[C@@H:46]([NH:50][C:51]([O:53][CH3:54])=[O:52])[CH:47]([CH3:49])[CH3:48])[NH:38][CH:39]=5)=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.FC(F)(F)C(O)=O>>[CH3:54][O:53][C:51](=[O:52])[NH:50][C@H:46]([C:45]([N:41]1[CH2:42][CH2:43][CH2:44][C@H:40]1[C:37]1[NH:38][CH:39]=[C:35]([C:32]2[CH:31]=[CH:30][C:29]([C:26]3[CH:27]=[CH:28][C:23]([C:21](=[O:22])[NH:20][C:17]4[CH:16]=[CH:15][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:19][CH:18]=4)=[CH:24][CH:25]=3)=[CH:34][CH:33]=2)[N:36]=1)=[O:55])[CH:47]([CH3:49])[CH3:48]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)Nc4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cc3)cc2)c[nH]1)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)Nc4ccc(N5CCNCC5)cc4)cc3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [4-{4-[(4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-biphenyl-4-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (42.4 mg, 0.0565 mmol) in dichloromethane (0.67 mL, 10 mmol) was added trifluoroacetic acid (0.3 mL, 0.004 mmol). The reaction mixture was stirred for 1 h at room temperature, concentrated, dissolved in methanol (1 mL), passed through a Stratospheres™ PL-CO3 resin, and the filtrate was concentrated to provide the title compound. (m/z): [M+H]+ calcd for C37H43N7O4 650.34 found 650.8.
Reaction SMILES: [CH3:1][C:2]1[C@@H](O)C[C@]2(O)C(C)(C)C=1[C@@H](O)C([C@@]1(C)[C@H]([C@@H]2OC(C2C=CC=CC=2)=O)[C@]2(OC(C)=O)CO[C@@H]2C[C@@H]1O)=O.[CH3:40]/[CH:41]=[C:42](/[C:44]([NH:46][C@H:47]([C@@H:54]([OH:99])[C:55]([O:57][C@@H:58]1[C:79]([CH3:80])=[C:78]2[C:81]([CH3:83])([CH3:82])[C@:60]([OH:98])([C@@H:61]([O:89][C:90]([C:92]3[CH:93]=[CH:94][CH:95]=[CH:96][CH:97]=3)=[O:91])[C@@H:62]3[C@:67]4([O:70][C:71]([CH3:73])=[O:72])[CH2:68][O:69][C@@H:66]4[CH2:65][C@H:64]([OH:74])[C@@:63]3([CH3:88])[C:75]([C@@H:77]2[O:84][C:85]([CH3:87])=[O:86])=[O:76])[CH2:59]1)=[O:56])[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:45])\[CH3:43]>>[CH3:80][C:79]1[C@@H:58]([O:57][C:55]([C@H:54]([OH:99])[C@@H:47]([NH:46][C:44]([C:42]2[CH:43]=[CH:1][CH:2]=[CH:40][CH:41]=2)=[O:45])[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:56])[CH2:59][C@:60]2([OH:98])[C:81]([CH3:82])([CH3:83])[C:78]=1[C@@H:77]([O:84][C:85]([CH3:87])=[O:86])[C:75]([C@@:63]1([CH3:88])[C@H:62]([C@@H:61]2[O:89][C:90]([C:92]2[CH:93]=[CH:94][CH:95]=[CH:96][CH:97]=2)=[O:91])[C@:67]2([O:70][C:71]([CH3:73])=[O:72])[CH2:68][O:69][C@@H:66]2[CH2:65][C@@H:64]1[OH:74])=[O:76]
Reactant: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](O)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Reactant: C/C=C(\C)C(=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](OC(C)=O)C(=C1C)C2(C)C
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Yield: 0.01 %

Procedure:
The solid was chromatographed as described under Example 1 except that RPLC C8 silica (100 g) was used in methanol/water 20%. A pressure of 50 psi was used to obtain an adequate rate. One hundred fifty fractions of 10 ml were collected, while a gradient of 25, 35, 45, 55 and 65% methanol in water was being used. The fractions were monitored as before and fractions containing 10-deacetylbaccatin III (fractions 25-35), brevitaxane A (fractions 60-90), cephalomannine (fractions 120-125) and taxol (fractions 135-150) were combined separately, concentrated to dryness and recrystallized from chloroform/hexane (1:1) to give the pure compounds. 10-deacetylbaccatin III, brevitaxane A, 2.0 g (0.2% yield, based on plant material), cephalomannine, 0.03 g (0.003% yield, based on plant material) and taxol 0.1 g (0.01% yield, based on plant material).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[C:20]4[O:25][CH2:24][O:23][C:21]4=[CH:22][C:17]=3[CH2:16][CH:15]([CH3:26])[N:14]([C:27](=[O:29])[CH3:28])[N:13]=2)=[CH:8][CH:7]=1)=[O:4].[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>>[CH2:30]([N:32]([CH2:33][CH3:34])[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[C:20]4[O:25][CH2:24][O:23][C:21]4=[CH:22][C:17]=3[CH2:16][CH:15]([CH3:26])[N:14]([C:27](=[O:29])[CH3:28])[N:13]=2)=[CH:8][CH:7]=1)=[O:4])[CH3:31]
Reactant: CC(=O)N1N=C(c2ccc(NC(=O)CCl)cc2)c2cc3c(cc2CC1C)OCO3
Reactant: CCNCC
Product: CCN(CC)CC(=O)Nc1ccc(C2=NN(C(C)=O)C(C)Cc3cc4c(cc32)OCO4)cc1

Procedure:
It was prepared from 1-(4-chloroacetylaminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine and diethylamine by using the process described in Example 102, m.p.: 175°-176° C.