Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([Sn](CCCC)(CCCC)CCCC)=[CH:5][CH:4]=[C:3]1[C:20]1[CH:21]=[C:22]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:28]1[CH:27]=[CH:26][C:25]([N:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:24][C:23]2=1.Br[C:53]1[S:57][C:56]([CH:58]=[O:59])=[CH:55][CH:54]=1>>[CH3:1][N:2]1[C:6]([C:53]2[S:57][C:56]([CH:58]=[O:59])=[CH:55][CH:54]=2)=[CH:5][CH:4]=[C:3]1[C:20]1[CH:21]=[C:22]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:28]1[CH:27]=[CH:26][C:25]([N:39]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:24][C:23]2=1
Reactant: O=Cc1ccc(Br)s1
Reactant: CCCCCCn1c2ccc(-c3ccc([Sn](CCCC)(CCCC)CCCC)n3C)cc2c2cc(N(c3ccccc3)c3ccccc3)ccc21
Product: CCCCCCn1c2ccc(-c3ccc(-c4ccc(C=O)s4)n3C)cc2c2cc(N(c3ccccc3)c3ccccc3)ccc21

Procedure:
As shown in scheme 3, 3,6-dibromo-9-hexyl-9H-carbazole (31) is reacted with 1-methyl-2-(tributylstannyl)-1H-pyrrole by Stille coupling reaction to obtain N-methyl-2-(3-bromo-9-hexyl-9H-carbazol-6-yl)pyrrole (32). Then, in the presence of sodium tert-butoxide, Pd(dba)2, and tri-tert-butyl phosphine, N-methyl-2-(3-bromo-9-hexyl-9H-carbazol-6-yl)pyrrole (32) is reacted with diphenylamine to obtain N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrole (33). n-butyl lithium is reacted with N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrole (33), and then tributylstannylchloride is added thereto to obtain N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)-5-tributyl-stannylpyrrole (34). N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)-5-tributylstannylpyrrole (34) is reacted with 5-bromo-2-thiophene-carboxaldehyde by Stille coupling reaction to obtain 5-[N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrol-5-yl]thiophene-2-carbaldehyde (35). Finally, 5-[N-methyl-2-(3-diphenylamino-9-hexyl-9y-carbazol-6-yl)pyrrol-5-yl]thiophene-2-carbaldehyde (35) is reacted with cyanoacetic acid in acetic acid by using ammonium acetate as a catalyst, and (E)-2-cyano-3-[5-(N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrol-5-yl)thiophen-2-yl]acrylic acid (36) is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([NH2:6])=O>O=P(Cl)(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1cc(Cl)c(Cl)nc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc(Cl)c(Cl)nc1Cl
Temperature: 90 °C
Yield: 99.2 %

Procedure:
A suspension of 2,5,6-trichloronicotinamide (Method 45, 2.3 g, 10.2 mmol) in POCl3 (20 ml) was heated to 90° C. for 1 hour. The reaction was then cooled to room temperature, and the POCl3 was removed under vacuum. The resulting residue was taken up in DCM (50 ml) and ice water (50 ml) was then added, followed by the careful addition of an aqueous solution of Na2CO3 until pH 8 was achieved. The organic fraction was then dried over Na2SO4, filtered, and concentrated to give the title compound (2.1 g, 80%) which was used without further purification. 1H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([OH:11])[CH:10]=1)[CH:6]=[CH2:7].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]1[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)[CH:10]=1)[CH:6]=[CH2:7]
Reactant: C1=COCCC1
Reactant: C=Cc1cc(O)cc(O)c1
Agent: Cl
Product: C=Cc1cc(OC2CCCCO2)cc(OC2CCCCO2)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
0.5 ml of concentrated hydrochloric acid is added to 80 g (587 mmol) of 3,5-dihydroxystyrene in 300 g of dihydropyran and the reaction mixture is stirred for 2 h at 40° C. The mixture is then poured into ice-water and extracted twice with ether. The organic phase is washed three times at 0° C. with 1N NaOH, dried, and concentrated by evaporation. The residue is purified by column chromatography (silica gel, hexane/ethyl acetate 4:1), giving 110 g (62%) of a viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9](C(O)=O)=[CH:10][C:6]=2[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[Cl:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])cc(Cl)c2s1
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: O=[N+]([O-])c1cc(Cl)c2sccc2c1
Temperature: 200 °C

Procedure:
To the suspension of acid (12.9 g, 0.05 mol) from step 2 in quinoline (200 ml) was added copper powder (5.2 g, 0.08 mol) and the mixture was heated at 200° C. for 2 h. The reaction mixture was cooled and extracted in ether. The ethereal layer was washed with 50% HCl, brine and dried over sodium sulphate and concentrated to yield 7-chloro-5-nitro-benzo[b]thiophene, 6.2 g which was used as such in Step 4, MS m/z 213 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=2[OH:15])=[CH:6][CH:7]=1.[CH2:16](Br)[CH:17]=[CH2:18]>>[CH2:18]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:9]([OH:15])[CH:10]=1)[CH:17]=[CH2:16]
Reactant: Oc1ccc(-c2ccc(Cl)nn2)c(O)c1
Reactant: C=CCBr
Product: C=CCOc1ccc(-c2ccc(Cl)nn2)c(O)c1

Procedure:
3-Chloro-6-(2,4-dihydroxyphenyl)pyridazine was reacted with allyl bromide under similar conditions to those described in Example 7a(i), to give 6-(4-allyloxy-2-hydroxyphenyl)-3-chloropyridazine.
Reaction SMILES: [C:1]1([CH2:9][C:10](OCC)=[O:11])([CH2:4][C:5](OC)=[O:6])[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)(C)C.Cl>C1COCC1>[C:1]1([CH2:9][CH2:10][OH:11])([CH2:4][CH2:5][OH:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC1(CC(=O)OC)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: OCCC1(CCO)CC1
Temperature: 25 °C

Procedure:
109.5 g (crude product, about 547 mmol) of ethyl methyl 2,2′-cyclopropane-1,1-diyldiacetate were dissolved in 750 ml of p.a. THF, and, at −20° C., 984 ml (984 mmol) of a 1 M solution of lithium aluminium hydride in THF were added dropwise. The reaction mixture was warmed to RT overnight and, after cooling again to −10° C., 500 ml of isopropanol were added carefully. The mixture was acidified with 1 N hydrochloric acid and filtered off with suction through Celite. The residue was washed with ethyl acetate and water. The filtrate was saturated with sodium chloride and extracted repeatedly with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated under reduced pressure. The residue was recrystallized from acetonitrile. This gave 50.4 g of the target product (70.8% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][S:16][C:17]1[N:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH:20]=[CH:19][N:18]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:30][C:27]2[CH:26]=[CH:25][C:24]([O:23][C:21]3[CH:20]=[CH:19][N:18]=[C:17]([S:16][CH3:15])[N:22]=3)=[CH:29][CH:28]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CSc1nccc(Oc2ccc(N)cc2)n1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CSc1nccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)n1
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A solution of 4.81 g (21.7 mmol) 4-chloro-3-trifluoromethyl-phenyl isocyanate in 100 ml THF was added within 45 min. drop by drop at 0° C. to a solution of 5.06 g (21.7 mmol) 4-(2-methylsulfanyl-pyrimidin-4-yloxy)-phenylamine and stirring continued at r.t. overnight. The reaction mixture was evaporated and leached with 100 ml dichloromethane. The precipitate was isolated and dried to give 8.53 g (86%) 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[4-(2-methylsulfanyl-pyrimidin-4-yloxy)-phenyl]-urea.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH2:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24]>C1(C)C=CC=CC=1>[Cl:19][CH2:20][CH2:21][NH:22][C:23]([NH:10][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:24]
Reactant: O=C=NCCCl
Reactant: NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: O=C(NCCCl)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide (prepared in Example 12, 182 mg, 0.64 mmol) in toluene (10 mL) was treated with 2-chloroethyl isocyanate (0.08 mL, 0.95 mmol). The reaction was heated at reflux for 16 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 1-(2-chloro-ethyl)-3-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionyl]-urea (189 mg, 76%) as a colorless oil: EI-HRMS m/e calcd for C17H21Cl3N2O2 (M+) 390.0669, found 390.0659.
Reaction SMILES: [CH:1]1([NH:7][C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19](Cl)[CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH2:31])=[O:30])=[CH:27][CH:26]=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.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]>[CH:1]1([NH:7][C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:31][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][C:25]([F:24])=[CH:26][CH:27]=4)[CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1CCCCC1)C1CCN(Cc2ccnc(Cl)c2)CC1
Reactant: NC(=O)c1ccc(F)cc1
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
Product: O=C(Nc1cc(CN2CCC(C(=O)NC3CCCCC3)CC2)ccn1)c1ccc(F)cc1
Temperature: 100 °C

Procedure:
A suspension of 1-(2-chloro-pyridin-4-ylmethyl)-piperidine-4-carboxylic acid cyclohexylamide (50 mg, 0.15 mol), 4-fluoro-benzamide (20 mg, 0.15 mmol) and Cs2CO3 (5 mg, 0.16 mmol) in degassed dioxane (3 mL) is treated with 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (17 mg, 0.030 mmol) and tris(dibenzylideneacetone)dipalladium(0) (6.8 mg, 0.007 mmol). The reaction mixture is heated overnight at 100° C. The mixture is filtered, evaporated, dissolved in MeCN (1 mL) and purified by prep HPLC E. The product is dissolved in 2 ml HCl 1.25 N in MeOH and re-evaporated at HV, delivering the title compound hydrochloride as a slightly yellow powder, LC-MS A: tR=0.67 min; [M+H]+=439.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH:9]=[CH2:10])=[CH:4][CH:3]=1.[ClH:12]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][Cl:12])=[CH:4][CH:3]=1
Reactant: C=CC(O)c1ccc(F)cc1
Reactant: Cl
Solvent: ClCCl
Product: Fc1ccc(C=CCCl)cc1
Reaction time: 1 h
Yield: 96 %

Procedure:
273.6 g (1.798 mol) of 1-(4-fluorophenyl)allyl alcohol were dissolved with stirring in 2,000 ml of methylene chloride. Subsequently, 101.0 g (2,770 mol) of hydrogen chloride were passed in over the course of 3 h, during which the temperature rose to 37° C. The mixture was then stirred for 1 h. After washing with 600 ml of ice-cold water and a mixture of 150 ml of saturated brine and 150 ml of water, the organic phase was dried over sodium sulfate and concentrated. 294.6 g (98%) of a brown oil were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[C:16]1([C:22]2[CH:23]=[CH:24][C:25](=O)[NH:26][N:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:15][C:2]1([CH3:1])[CH:3]=[C:4]([O:14][C:25]2[N:26]=[N:27][C:22]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:23][CH:24]=2)[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=2)[O:11]1
Reactant: O=c1ccc(-c2ccccc2)n[nH]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Product: CC1(C)C=C(Oc2ccc(-c3ccccc3)nn2)c2cc(C#N)ccc2O1

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 6-phenyl-2H-pyridazin-3-one as starting materials, the title compounds were prepared as white solids.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:24]3[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=3[Cl:22])[CH2:35][CH2:34]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Clc1cccc(Cl)c1N1CCNCC1
Product: CCc1cc(NC(=O)N2CCN(c3c(Cl)cccc3Cl)CC2)c(OC)nc1C
Yield: 80 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,6-dichlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: CN(C)[CH:3]=[O:4].[H-].[Na+].Br[CH2:9][CH:10]([N:17]1[C:21]2[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:20]=2[N:19]=[C:18]1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Cl>C(OCC)(=O)C>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:18]2[N:17]([CH:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:9][O:4][C:3]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[F:26])[C:21]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:20]=3[N:19]=2)=[CH:33][CH:32]=1
Reactant: CN(C)C=O
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(CBr)C3CCCCC3)c2cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COc3ccccc3F)C3CCCCC3)c2cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9 %

Procedure:
To a solution of 27 mg (0.24 mmol) 2-fluorophenole in 2 mL N,N-dimethylformamide 11 mg (0.24 mmol, 55% dispersion in mineral oil) sodium hydride were added and the reaction mixture stirred for 10 min. at room temperature. To the suspension 100 mg (0.22 mmol) 1-(2-bromo-1-cyclohexyl-ethyl)-2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole were added. The reaction mixture was stirred for 18 h at room temperature, and then poured on 30 mL 1N hydrochloric acid and 30 mL ethyl acetate. The phases were separated and the aqueous layer extracted a second time with 30 mL ethyl acetate. The combined organic layers were washed twice with 30 mL water and once with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate 100:0 to 70:30) to give the desired compound as white solid (9%). MS (Turbo Spray): m/z=485.3 [M+H].
Reaction SMILES: [C:1]([C:5]1[C:6]([O:28][CH3:29])=[C:7]([C:19]#[C:20][C:21]2[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH:8]=[C:9]([C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[OH-].[OH-].[Pd+2].CCOC(C)=O.CO>[C:1]([C:5]1[C:6]([O:28][CH3:29])=[C:7]([CH2:19][CH2:20][C:21]2[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH:8]=[C:9]([C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ncccc1-c1cc(C#Cc2ccc(N)cn2)c(OC)c(C(C)(C)C)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ncccc1-c1cc(CCc2ccc(N)cn2)c(OC)c(C(C)(C)C)c1
Yield: 56.2 %

Procedure:
step 2—A suspension of 180 (0.322 g, 0.831 mmol) 20% Pd(OH)2/C (0.146 g) and EtOAc/MeOH (1:1, 40 mL) was hydrogenated in a Parr Shaker under 50 psi of hydrogen for 2 h. The resulting suspension was filtered through CELITE and evaporated. The crude product was purified by SiO2 chromatography eluting with a EtOAc/hexane gradient (0 to 90% EtOAc) to afford 0.183 g of 6-{2-[3-tert-butyl-2-methoxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-pyridin-3-ylamine (182) as a yellow foam.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10](=[O:22])[C:11]3[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]([OH:21])=[O:20])=[CH:13][CH:12]=3)=[C:8]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[S:7][C:6]=2[CH:30]=1>CCO.CCOC(C)=O.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10](=[O:22])[C:11]3[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:16]=3)=[C:8]([C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)[S:7][C:6]=2[CH:30]=1
Reactant: O=C(O)C=Cc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)CCc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Yield: 72.7 %

Procedure:
6-hydroxy-3-[4-(2-carboxyvinyl)benzoyl]-2-(4-hydroxyphenyl)benzo[b]thiophene (310 mg, 0.74 mmol) was dissolved in 50 mL of a 1:1 mixture of EtOH and EtOAc. This solution was hydrogenated at 40 psi in the presence of 10% Pd/C (200 mg). When the reaction was judged complete by TLC analysis, the mixture was filtered through Celite to remove the catalyst. The filtrated was concentrated in vacuo to a yellow oil that was triturated from hexanes/EtOAc. Filtration provided 225 mg (72%) of 6-hydroxy-3-[4-(2-carboxyethyl)benzoyl]-2-(4-hydroxyphenyl)benzo[b]thiophene as a yellow solid. mp 244-248° C. 1H NMR (DMSO-d6) δ 12.15 (bs, 1H), 9.74 (S, 1H), 9.68 (S, 1H), 7.56 (d, J=8.1 Hz, 2H), 7.30 (d, J=2.0 Hz, 1 H), 7.23-7.19 (m, 3H), 7.12 (d, J=8.5 Hz, 2H), 6.82 (dd, J=9.0, 2.0 Hz, 1H), 6.62 (d, J=8.5 Hz, 2H), 2.77 (t, J=7.0 Hz, 2H), 2.45 (t, J=7.0 Hz, 2). FD mass spec: 418. Anal. Calcd. for C24H18O5S.20 H2O: C, 68.89; H, 4.34. Found: C, 68.35; H, 4.72.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].ClC(Cl)(Cl)C[O:66][C:67](Cl)=[O:68]>N1C=CC=CC=1.ClCCl>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([O:40][C:5]([CH2:4][CH2:3][CH2:2][C:67]([OH:66])=[O:68])=[O:6])[C@@H:24]([NH:31][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: 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
Solvent: ClCCl
Solvent: c1ccncc1
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](OC(=O)CCCC(=O)O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Temperature: -20 °C
Reaction time: 2 h

Procedure:
875 mg of paclitaxel was dissolved in 6 ml of pyridine and 40 ml of dichloromethane. The solution was cooled at −20° C. Three hundred microliters of trichloroethylchloroformate (Troc) (at −20° C.) was added by portions of 100 microliters and the solution was kept at −20°C. for two hours. An additional 100 microliters of Troc was added and the solution was stirred at room temperature for 20 hours. The solvent was evaporated to dryness. The residue was dissolved in 10 ml of dimethylformamide with 1.36 g of glutaric anhydride and 40 mg of dimethylaminopyridine. The solution was stirred at 85° C. for 20 hours. The product was precipitated with 10 volumes of water. The white precipitate was collected on a sintered glass filter and dried. The dried product was then dissolved in 20 ml of methanol:acetic acid (9:1) and 0.5 g of zinc powder was added. The solution was stirred at room temperature for 30 minutes. Zinc was filtered and the filtrate was evaporated to a volume of about 2 ml. 70 ml of dichloromethane was added and the solution was washed twice with 30 ml of 0.01N HCl, once with 30 ml of sodium bicarbonate and once with 50 ml of water. The organic phase was dried with anhydrous sodium sulfate, filtered and evaporated to dryness. This yielded 620 mg of a C7-glutaryl paclitaxel
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:22]([O:24]CC)=[O:23])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1.O.[OH-].[Li+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:22]([OH:24])=[O:23])=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[N:13]=1
Reactant: CCOC(=O)c1oc(-c2c(F)cccc2F)nc1-c1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2nc(-c3c(F)cccc3F)oc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
To a stirred solution of ethyl 2-(2,6-difluorophenyl)-4-(4-methoxyphenyl)oxazole-5-carboxylate (0.030 g, 0.08 mmol) in THF and H2O (1:1, 3 mL) was added lithium hydroxide hydrate (0.008 g, 0.33 mmol) and the reaction mixture stirred at room temperature for 2.5 hours. The THF was removed in vacuo and 1N aqueous HCl was added and the resultant precipitate collected by filtration to afford 2-(2,6-difluorophenyl)-4-(4-methoxyphenyl)oxazole-5-carboxylic acid (0.027 g, 0.08 mmol, 98%) as a white solid which was used without further purification. LCMS (1) Rt: 1.24 min; m/z (ES+) 332.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:11])=[C:4]([NH:8][CH2:9][CH3:10])[N:5]=[N:6][CH:7]=1.[CH2:12](OC(OCC)OCC)C>>[Cl:1][C:2]1[C:3]2[N:11]=[CH:12][N:8]([CH2:9][CH3:10])[C:4]=2[N:5]=[N:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: CCNc1nncc(Cl)c1N
Product: CCn1cnc2c(Cl)cnnc21
Yield: 45 %

Procedure:
A mixture of 5-chloro-N3-ethyl-pyridazine-3,4-diamine (Preparation 7, 10.0 g, 58 mmol) and triethylorthoformate (60 mL) were heated to reflux for 4 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (50 mL) and filtered. The filter cake was washed with EtOAc and then the organic layers were washed with saturated brine solution, dried over Na2SO4 and concentrated in vacuo to afford the title compound as a yellow solid in 45% yield, 4.8 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH3:12])[CH:6]=[C:5]2[C:13]#[N:14].[S:15]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16]1.[F-].[Cs+]>C([O-])(O)=O.[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:17]3[CH:18]=[CH:19][S:15][CH:16]=3)=[CH:10][CH:9]=2)[C:5]([C:13]#[N:14])=[CH:6]1)[CH3:12]
Reactant: CCn1cc(C#N)c2cc(Br)ccc21
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Cs+]
Product: CCn1cc(C#N)c2cc(-c3ccsc3)ccc21
Temperature: 90 °C
Yield: 24.8 %

Procedure:
A tube was charged with a mixture of 5-bromo-1-ethyl-1H-indole-3-carbonitrile (100 mg, 0.40 mmol), thiophene-3-boronic acid (72 mg, 0.56 mmol), PdCl2(PPh3)2 (11 mg, 0.016 mmol) and CsF (152 mg, 1 mmol) and then alternately evacuated and filled with nitrogen (3×) and diluted with dimethoxyethane (3 mL) and then heated to 90° C. for 19 h. After cooling, the crude reaction mixture was diluted with saturated NaHCO3 and extracted with EtOAc (2×). The combined organic phases were washed with saturated NaCl and dried and concentrated. Flash chromatography over silica gel (CH2Cl2/hexanes, 40/60) gave 25 mg (25%) of 1-ethyl-5-thiophen-3-yl-1H-indole-3-carbonitrile as a white solid.