Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=C(S(O[C@@H:14]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:16]([C:26]([O:28][CH3:29])=[O:27])[CH2:15]2)(=O)=O)C=CC=1)([O-])=O.C(#N)CC.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[SH:41].C(N(CC)CC)C>C([O-])([O-])=O.[Na+].[Na+]>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41][C@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@H:16]([C:26]([O:28][CH3:29])=[O:27])[CH2:15]1
Reactant: Sc1ccccc1Cl
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2cccc([N+](=O)[O-])c2)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](Sc2ccccc2Cl)CN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Under an atmosphere of argon, (2S,4S)-1-tert-butyl 2-methyl 4-(3-nitrophenylsulfonyloxy)pyrrolidine-1,2-dicarboxylate (8.5 g, 19.7 mmol, Eq: 1.00) was combined with propionitrile (82.0 ml) to give a light brown solution. Then 2-chlorobenzenethiol (4.28 g, 3.38 ml, 29.6 mmol, Eq: 1.50) and triethylamine (4.00 g, 5.5 ml, 39.5 mmol, Eq: 2.00) were added dropwise. The reaction was stirred overnight at reflux (100° C.). The reaction was cooled to room temperature, and poured in 50 ml Na2CO3 solution (10%), and extracted with 2×100 ml ethyl acetate. The organic layers were washed with 50 ml HCl 0.1M and 50 ml satd. NaCl solution. The organic layer was stirred over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (70 g column, from 100% to 80% heptane in ethyl acetate). The title compound was obtained as a yellow oil (5.7 g, 77.6%, MS (m/e)=372.1 [M+H+]).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]#[N:12])[NH:7][CH:6]=[C:5]2[CH:13]=O.C1(P(=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[C:11]([C:10]1[CH:9]=[C:8]2[C:4]([C:5](/[CH:13]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:6][NH:7]2)=[CH:3][C:2]=1[F:1])#[N:12]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cc2[nH]cc(C=O)c2cc1F
Solvent: CC#N
Product: CCOC(=O)/C=C/c1c[nH]c2cc(C#N)c(F)cc12
Temperature: 90 °C

Procedure:
To a solution of 5-fluoro-3-formyl-1H-indole-6-carbonitrile (D152) (250 mg) in acetonitrile (30 mL) was added ethyl (triphenylphosphoranylidene)acetate (926 mg). The reaction mixture was refluxed at 90° C. for 24 hours. The solvent was then evaporated and the residue was chromatographed on silica gel eluting with EA and PA (3:7-7:3) to generate ethyl (2E)-3-(6-cyano-5-fluoro-1H-indol-3-yl)-2-propenoate (D153) (275 mg). MS (ES): C14H11FN2O2 requires 258.1; found 259.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:15][C@@H:16]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C@@H:17]([OH:31])[C:18]([O:20]C1(C)CCC(C(C)C)CC1)=[O:19].[OH-].[K+]>CO.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[S:15][C@@H:16]([C:32]1[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=1)[C@@H:17]([OH:31])[C:18]([OH:20])=[O:19]
Reactant: COc1ccc([C@H](Sc2cc(Oc3ccccc3)ccc2N)[C@@H](O)C(=O)OC2(C)CCC(C(C)C)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc([C@H](Sc2cc(Oc3ccccc3)ccc2N)[C@@H](O)C(=O)O)cc1
Yield: 65.2 %

Procedure:
4.2 g of l-menthyl (2S, 3S)-3-(2-amino-5-phenoxyphenyl)thio-2-hydroxy-3-(4- methoxyphenyl)propionate [prepared as described in step (a) above] were suspended in 42 ml of methanol, and a solution of 0.89 g of caustic potash dissolved in 5 ml of water was added to the resulting suspension. The resulting mixture was then stirred under reflux for 1 hour. At the end of this time, the methanol was removed by evaporation under reduced pressure, and 60 ml of Water and 60 ml of diethyl ether were added to the residue. The resulting mixture was stirred, and the ethereal layer was then removed. Ethyl acetate was added to the aqueous layer. after which 14.5 ml of 1N aqueous hydrochloric acid were added to neutralize the mixture. The ethyl acetate layer was then separated and dried over anhydrous anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the residual gum Was crystallized using diethyl ether and diisopropyl ether. The crystals obtained were collected by filtration to afford 2.05 g of the title compound. melting at 151-152° C.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[N+](=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][O:4][CH:2]([CH3:3])[CH3:1])[CH3:12]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)O
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)COC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
To a solution of 2-propanol (0.776 mL, 10.0 mmol) in dichloromethane (33 mL) is added rhodium (II) acetate dimer (22 mg) followed by ethyl diazoacetate (1.05 mL, 10.0 mmol). The reaction mixture is stirred at RT for 30 min. The reaction mixture is filtered through Celite, and the filtrate is evaporated and the residue is vacuum distilled at 150° C. to give 750 mg of the product 405. 1H NMR (CDCl3) δ 4.21 (q, 2 H), 4.06 (s, 2 H), 3.73 (m, 1 H), 1.29 (t, 3 H), 1.22 (s, 3 H), 1.19 (s, 3 H); MS: m/z 147 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([C:14]([O:16]C)=[O:15])=[C:6]2[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1.[OH-].[Na+].CO.Cl>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([C:14]([OH:16])=[O:15])=[C:6]2[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1
Reactant: COC(=O)c1[nH]c2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2c(C(=O)O)[nH]c3cc(OC)c(OC)cc23)cc1OC
Yield: 85.3 %

Procedure:
A mixture of methyl 5,6-dimethoxy-3-(3,4-dimethoxyphenyl)indole-2-carboxylate (0.54 g), 2N-NaOH (10 ml) and methanol (25 ml) was refluxed for 3 hours under stirring. The reaction mixture was poured into water, acidified with 6N-HCl and extracted with chloroform. The chloroform layer was washed with water, dried (MgSO4) and concentrated. The precipitated crystals were collected by filtration and recrystallized from methanol to give 5,6-dimethoxy-3-(3,4-dimethoxyphenyl)indole-2-carboxylic acid (0.443 g, 85%) as pale red prisms.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([I:22])=[N:17][N:16]=[C:15]3I)=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:26][O-:27].[Na+].Cl>CN(C=O)C>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([I:22])=[N:17][N:16]=[C:15]3[O:27][CH3:26])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: C[O-]
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc2c(I)nnc(I)c2c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nnc(I)c2ccc(C(=O)Nc3cccc(C(F)(F)F)c3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.3 %

Procedure:
A mixture of 1,4-di-iodo-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (0.59 g, 1.037 mmol), sodium methoxide (0.11 g, 2.036 mmol) in DMF (8 mL) was stirred at room temperature for 18 hours. The reaction was poured onto water, neutralized with 2N HCl. The product was extracted with EtOAc (×3), the combined organic extracts washed with water (×3), brine and dried (Na2SO4). Chromatography (Hex/EtOAc) afforded 1-iodo-4-methoxy-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (134 mg), m/z 473.91; and 4-iodo-1-methoxy-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (132 mg), m/z 473.91.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:18]2[C:19]([CH3:31])([CH3:30])[C:20](=[O:29])[N:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:22]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:32][C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:18]2[C:19]([CH3:31])([CH3:30])[C:20](=[O:29])[N:21]([CH:23]3[CH2:24][CH2:25][N:26]([S:39]([C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([CH3:32])[CH:34]=4)(=[O:41])=[O:40])[CH2:27][CH2:28]3)[N:22]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OCc1ccccc1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc(C)c4)CC3)C(=O)C2(C)C)cc1OCc1ccccc1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-[3-(benzyloxy)-4-methoxyphenyl]-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B4*HCl) and 3-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1.[CH3:25][S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27].CS(C)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:20][CH2:21][N:22]([CH2:30][CH2:29][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:23][CH2:24]2)[CH2:15][CH2:14]1
Reactant: C=CS(C)(=O)=O
Reactant: COc1cc(N2CCC(N3CCNCC3)CC2)c(Cl)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1cc(N2CCC(N3CCN(CCS(C)(=O)=O)CC3)CC2)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
1-{1-[2-Chloro-5-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (Example 112, step D) (0.050 g, 1.41 mmol) was taken up in THF (10 mL) and methylvinylsulfone (0.371 mL, 4.23 mmol) was added. DMSO was added to solubilize the starting material. Reaction was stirred overnight at rt. Reaction was not complete and over the next 3 days, 30 equivalents more methylvinylsulfone were added. Reaction was then stirred over the weekend. Poured reaction mixture onto prepackaged silica gel cartridge, dried by vacuum suction of air through cartridge and then flash chromatographed to give the title compound of step A (0.370 g, 57%). MS (M+H, ES+) 461.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:9](Cl)=[O:10].[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14]1>>[C:20]1([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][CH:13]([NH:12][C:9]([C@@H:2]3[CH2:3][CH:4]4[CH2:7][CH2:8][N:1]3[CH2:6][CH2:5]4)=[O:10])[CH2:14]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)C1CC2CCN1CC2
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Product: O=C(NC1CCN(CCc2ccccc2)C1)[C@@H]1CC2CCN1CC2

Procedure:
Quinuclidine-2-carbonyl chloride and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)quinuclidine-2-carboxamide.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:11]([CH3:12])=[CH:10][C:9]([Br:13])=[CH:8][N:7]=1.S(=O)(=O)(O)[OH:15]>O>[Br:13][C:9]1[CH:10]=[C:11]([CH3:12])[C:6]([OH:15])=[N:7][CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(Br)cnc1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)cnc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
Sodium nitrite (5.0 g, 72.5 mmol) in water (10 mL) was added dropwise to a cooled (0° C.) mixture of 2-amino-5-bromo-3-methylpyridine (5.0 g, 26.7 mmol; Lancaster) in 2:6 M sulfuric acid (70 mL). The mixture was allowed to warm to ambient temperature, stir for 1.5 hours, filtered, and the filtercake was washed with cold water and air dried. The precipitate was dissolved in dichloromethane (100 mL), dried (MgSO4), and concentrated to provide the title compound as a solid (4.2 g, 84%). MS (DCI/NH3) m/z 348 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[N:32][OH:33])[CH2:30][CH3:31])=[CH:25][CH:24]=1.[C:34]([O:41][CH2:42][CH3:43])(=[O:40])[C:35]([O:37]CC)=O>C1COCC1>[OH:33][N:32]=[C:29]([C:26]1[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)[CH:30]([CH3:31])[C:35](=[O:37])[C:34]([O:41][CH2:42][CH3:43])=[O:40]
Reactant: CCC(=NO)c1ccc(OC)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(=O)C(C)C(=NO)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
Diisopropylamine (22 mL, 154 mmol) was added to 60 mL of THF and cooled with an external ice bath. Butyllithium (59 mL, 147 mmol, 2.5 M in hexanes) was added and the mixture was stirred at 0° C. for 30 min, and brought to room temperature. The resulting LDA solution was added to a mixture of 1-(4-methoxyphenyl)propan-1-one oxime (12 g, 67.0 mmol) and THF (60 mL) at 0° C. Following the addition, the reaction mixture was stirred at 0° C. for 1 hour and warmed to room temperature. The mixture was then transferred to a syringe and added dropwise to a flask containing a pre-cooled mixture of diethyl oxalate (46 mL, 335 mmol) and THF (150 mL) at 0° C. After the addition was complete, the reaction mixture was stirred at room temperature for 18 hours. The mixture was cooled in an ice bath and quenched with 200 mL of 10% hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with EtOAc. The aqueous layer was then neutralized with solid sodium bicarbonate and extracted further with CH2Cl2. The organic layers were combined, dried over MgSO4 and concentrated. The crude oil was purified by chromatography (0-40% EtOAc/hexanes) to give 17.7 g of the title compound. MS: (+) m/z 280 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:19][CH2:18]2)[N:11]=3)[CH:5]=[C:4]([CH3:26])[C:3]=1[OH:27].[F-].[Cs+].[CH2:30]1[O:32][C@@H:31]1[CH2:33][OH:34]>CN(C=O)C>[CH3:26][C:4]1[CH:5]=[C:6]([C:8]2[S:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][CH2:19]2)[N:11]=3)[CH:7]=[C:2]([CH3:1])[C:3]=1[O:27][CH2:30][C@H:31]([OH:32])[CH2:33][OH:34]
Reactant: OC[C@@H]1CO1
Reactant: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc(C)c1O
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc(C)c1OC[C@H](O)CO
Temperature: 80 °C

Procedure:
A mixture of 2,6-dimethyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenol (35.1 mg, 94 μmol) and cesium fluoride (0.72 mg, 4.7 μmol) in anhydrous DMF (0.5 mL) was stirred at 25° C. for 1 h. (R)-(+)-glycidol (98% ee) (6.6 μl, 99 μmol) was then added, and the resulting mixture was heated under argon at 80° C. for 2 d. Additional (R)-(+)-glycidol (6.56 μl, 98.9 μmol) was then added, and the reaction mixture was heated at 80° C. for 18 h. The reaction mixture was subsequently cooled to 25° C., filtered through Celite, diluted with DMSO (1.5 mL), and purified by rpHPLC (10-100% CH3CN/water+0.1% TFA) to provide (R)-3-(2,6-dimethyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenoxy)propane-1,2-diol as a white solid. MS (ESI) m/z: Calculated: 446.2; Observed: 447.0 (M++1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[C:4]([CH3:8])=[N:3]1.Cl[C:10]1[CH:15]=[C:14]([NH:16][C:17]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:18]=2[C:19]([NH:21][CH3:22])=[O:20])[C:13]([Cl:28])=[CH:12][N:11]=1>>[Cl:28][C:13]1[C:14]([NH:16][C:17]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:18]=2[C:19]([NH:21][CH3:22])=[O:20])=[CH:15][C:10]([NH:7][C:5]2[C:4]([CH3:8])=[N:3][N:2]([CH3:1])[CH:6]=2)=[N:11][CH:12]=1
Reactant: Cc1nn(C)cc1N
Reactant: CNC(=O)c1cc(F)ccc1Nc1cc(Cl)ncc1Cl
Product: CNC(=O)c1cc(F)ccc1Nc1cc(Nc2cn(C)nc2C)ncc1Cl

Procedure:
1,3-Dimethyl-1H-pyrazol-4-amine and 2-(2,5-dichloropyridin-4-ylamino)-5-fluoro-N-methylbenzamide were reacted according to the procedure of example 3.40 to afford 2-(5-chloro-2-(1,3-dimethyl-1H-pyrazol-4-ylamino)pyridin-4-ylamino)-5-fluoro-N-methylbenzamide (16.1 mg) as a beige solid. 1H NMR spectrum: (300 MHz, DMSO) δ 2.06 (3H, s), 2.77 (3H, d), 3.69 (3H, s), 6.60 (1H, s), 7.40 (1H, m), 7.55 (2H, m), 7.81 (1H, s), 7.93 (1H, s), 8.01 (1H, s), 8.72 (1H, m), 9.70 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+ =389
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH2:27]([N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40])[CH:28]=[CH2:29].C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:40]=[C:31]1[C:32]2[C:33](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34](=[O:35])[N:30]1[CH2:27]/[CH:28]=[CH:29]/[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:12]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][CH:18]=3)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: C=CCN1C(=O)c2ccccc2C1=O
Reactant: O=C(Nc1ccc(I)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(/C=C/CN2C(=O)c3ccccc3C2=O)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 50.6 %

Procedure:
A mixture of intermediate (1) (0.012 mol), N-allyl-phthalimide (0.012 mol), palladium(II) acetate (0.001 mol) and triethylamine (0.024 mol) was stirred at 100° C. for 12 hours in a bomber, then dissolved in DCM and washed with K2CO3 10%. The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue was crystallized from ACN. The precipitate was filtered off and dried, yielding 3.2 g of N-[4-[(1E)-3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-propenyl]phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide (intermediate 2; mp. 190° C.).
Reaction SMILES: Br[C:2]1[C:3]([C:21]([O:23][CH3:24])=[O:22])=[C:4]([NH:7][C:8](=[O:20])[CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[CH:15]3)[S:5][CH:6]=1.[C:25]([Cu])#[N:26].[NH4+].[OH-].C(OCC)C>CN(C=O)C>[C:25]([C:2]1[C:3]([C:21]([O:23][CH3:24])=[O:22])=[C:4]([NH:7][C:8](=[O:20])[CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[CH:15]3)[S:5][CH:6]=1)#[N:26]
Reactant: COC(=O)c1c(Br)csc1NC(=O)Cc1cccc2cnccc12
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1c(C#N)csc1NC(=O)Cc1cccc2cnccc12
Temperature: 100 °C

Procedure:
To a stirring mixture of methyl 4-bromo-2-(2-(isoquinolin-5-yl)acetamido)thiophene-3-carboxylate (100 mg) in DMF (0.5 mL) was added CuCN (150 mg). The resulting mixture was heated to 100° C. overnight. The reaction mixture was cooled to room temperature. To this mixture was added a 10% NH4OH solution and ethyl ether. The crude mixture was stirred at rt for 1 h. A normal aqueous workup with ethyl ether was followed. The organic layers were dried over MgSO4, filtered and concentrated under reduce pressure. The crude product mixture was purified by silica gel column chromatography to give methyl 4-cyano-2-(2-(isoquinolin-5-yl)acetamido)thiophene-3-carboxylate. Method[1], MS (ESI) 352.0 [M+H], Retention time=1.343 min.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:7]=[C:8](O)[CH:9]=1)[CH2:5][OH:6].[C:11]([O-:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:5]([O:19][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:6])[C:4]1[CH:7]=[CH:8][CH:9]=[CH:2][CH:3]=1
Reactant: O=C([O-])c1ccccc1
Reactant: OCc1cc(O)cc(O)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(OC(=O)c1ccccc1)c1ccccc1

Procedure:
The synthesis of organotelluride catalysts based on 3,5-dihydroxybenzyl alcohol (1) is shown in FIG. 11. 3,5-Bis[3-(tert-butyldimethylsilyloxy)propyl-1-oxy]benzyl alcohol (5) (Francavilla et al., J. Am. Chem. Soc., 123:57 et al. (2001), which is hereby incorporated by reference in its entirety) was converted to the corresponding benzoate 6 in 99% isolated yield with benzoic anhydride and pyridine in the presence of catalytic DMAP. The silyl protecting groups were removed with HF-pyridine to give diol 7 in 89% isolated yield. Diol 7 was converted to the corresponding dibromide 8 in two steps (Wendler et al., Tetrahedron, 3:144 et al. (1958), which is hereby incorporated by reference in its entirety). The mesylate was first prepared, but not isolated, and was then treated in situ with lithium bromide to give dibromide 8 in 87% isolated yield. The addition of PhTeNa to 8 gave 9a with two phenyltelluro groups in 65% isolated yield; 4-Me2NC6H4TeNa, 9b with two dimethylaminophenyltelluro groups in 92% isolated yield; and n-C6H13TeNa, 9c with two hexyltelluro groups in 62% isolated yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:33])[C@@H:13]([NH:22]C(OCC2C=CC=CC=2)=O)[CH2:14][CH:15]2[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:33])[C@@H:13]([NH2:22])[CH2:14][CH:15]2[CH2:19][O:18][C:17]([CH3:20])([CH3:21])[O:16]2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC2COC(C)(C)O2)NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)CC2COC(C)(C)O2)CC1
Reaction time: 12 h

Procedure:
To a solution of 612 mg 4-[(S)-2-Benzyloxycarbonylamino-3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-propionyl]-piperazine-1-carboxylic acid ethyl ester in 15 ml ethyl acetate were added 200 mg Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (1 bar) for 12 h. The reaction mixture was filtered over a plug of Celite, washed with ethyl acetate, concentrated and the crude product used without further purification. Yield: 344 mg.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:33])[C:18]=3[C:22]([NH:24][CH2:25][CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:23])[N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[K+]>O>[Cl:33][C:17]1[C:18]([C:22]([NH:24][CH2:25][CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[O:23])=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([N:9]1[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1)[CH:21]=[CH:20]2
Reactant: CCOC(=O)C1CCN(c2ccc3c(C(=O)NCCC4CCCCC4)c(Cl)ccc3n2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(NCCC1CCCCC1)c1c(Cl)ccc2nc(N3CCC(C(=O)O)CC3)ccc12
Temperature: 70 °C
Yield: 79.7 %

Procedure:
To a 10 mL vial was added 1-[6-chloro-5-[[(2-cyclohexylethyl)amino]carbonyl]-2-quinolinyl]-4-piperidinecarboxylic acid ethyl ester (Example 76(d)) (200 mg), methanol (2 mL) and potassium hydroxide (100 mg) in water (1 mL)). The vial was sealed and heated at 70° C. in a microwave for 10 minutes. The mixture was concentrated and the residue was acidified to pH 5 with aqueous 2 M hydrochloric acid. The resulting solid was collected by filtration. Purification (Varian NH2 cartridge using methanol:dichloromethane 1:1 (100 mL) and then 2% acetic acid in methanol:dichloromethane 1:1(100 mL) as eluant) afforded the title compound (150 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+]>CO.[Pd]>[CH:5]1([C:8]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10][CH2:9]2)[CH2:4][CH2:3][CH2:2][CH2:7][CH2:6]1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)C1(C2CCCCC2)CCC1
Reaction time: 1 h

Procedure:
A mixture of 2.04 g 1-(4-chloro-phenyl)-cyclobutanecarboxylic acid [50921-39-6], 0.875 g sodium acetate and 0.20 g 10% Pd/C in 15 ml of methanol is hydrogenated at room temperature and 0.1 bar for 1 hour. The catalyst is removed by filtration over Hyflo and the filtrate is charged with 0.20 g of Nishimura's catalyst. The mixture is hydrogenated at room temperature and 4 bar for 1.5 hours. The catalyst is removed by filtration over Hyflo and concentrated by evaporation to provide the title compound as a colourless oil which is used without further purification. Rt=4.44 (gradient I).