Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[O:12]1[CH:18]2[CH:13]1[CH:14]=[CH:15][CH2:16][CH2:17]2>[Pd].O1CCCC1>[OH:12][CH:13]1[CH2:18][CH2:17][CH:16]=[CH:15][CH:14]1[N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: C1=CC2OC2CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C1C=CCCC1O

Procedure:
If 19.11 g (0.13 mol) of phthalimide are reacted with 0.6 mol % of the palladium(0) catalyst prepared in situ as described above and one equivalent of 3,4-epoxycyclohexene in tetrahydrofuran first at 0° C. and then for 4 hours at the reflux temperature, 1.45 g (4.6% of theory) of [(1RS,2SR)-2-hydroxy-1-phthalimido-cyclohex-5-ene of melting point 112° to 114° C. are obtained after purification by chromatography over silica gel using ethyl acetate/cyclohexane 3/2. 1H NMR (270 MHz, d6 -DMSO); δ[ppm]: 7.83 (m, 4H), 5.90 (m, 1H), 5.63 (m, 1H), 4.84 (d, 1H), 4.75 (m, 1H), 3.90 (m, 1H), 2.27 (m, 1H), 2.1-1.65 (m, 3H).
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:10])[CH2:8][OH:9])[C@H:4]([C:11]([NH2:13])=[O:12])[CH2:3]1.N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C)C=O>[F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:10])[CH2:8][O:9][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:4]([C:11]([NH2:13])=[O:12])[CH2:3]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(=O)N1C[C@@H](F)C[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
(2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxa mide (4.10 g) and imidazole (3.27 g) were dissolved in dehydrated N,N-dimethylformamide (100 mL). While the solution was cooled in an ice bath, a solution of tert-butyldimethylsilyl chloride (3.62 g) in dehydrated N,N-dimethylformamide (30 mL) was added dropwise and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure and dissolved in ethyl acetate (300 mL). The ethyl acetate solution was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=ethyl acetate:methanol=10:1) to give (2S,4S)-4-fluoro-1-[2-(tert-butyldimethylsilyloxy)acetyl]pyrro lidine-2-carboxamide as a white solid (6.17 g).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].C(=O)([O-])O.[Na+].[C:21](OC)(=[O:24])[C:22]#[CH:23]>ClCCl.CO>[C:8]([C:7]1[CH:23]=[CH:22][C:21](=[O:24])[N:2]2[CH:6]=[CH:5][NH:4][C:3]=12)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#CC(=O)OC
Reactant: O=C(Cc1ncc[nH]1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccccc1)c1ccc(=O)n2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
500 mg (2.25 mmol) of 2-(1H-Imidazol-2-yl)-1-phenylethanone hydrochloride (example L, step 1) are suspended in dichlormethane. Sodium hydrogen carbonate is added to the suspension and stirred for 1 h at rt. The suspension is filtrated and the solvent is evaporated under vacuum to yield the free base. The crude is dissolved in 3 ml methanol. 188.78 mg (2.25 mmol) of methyl propiolate are added dropwise to the solution. The mixture is stirred for 24 h at rt. The suspension is filtrated and the precipitate is washed with methanol and diethylether to yield 214 mg (40.0% of th.) 8-Benzoylimidazo[1,2-a]pyridin-5(1H)-one.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].[Cl:8][C:9]1[C:14]([F:15])=[C:13](Cl)[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:13]1[C:14]([F:15])=[C:9]([Cl:8])[N:10]=[CH:11][N:12]=1)[C:4]#[C:5][CH3:6]
Reactant: Fc1c(Cl)ncnc1Cl
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1ncnc(Cl)c1F
Reaction time: 0.17 h
Yield: 86.2 %

Procedure:
0.61 g of sodium hydride (60% oil suspention) was suspended in 20 ml of tetrahydrofuran. 1 ml of tetrahydrofuran solution of 0.73 g of 2-butyn-1-ol was added dropwise at 0° C. therein, and the mixture was stirred for 10 minutes. Into the mixture was added dropwise 5 ml of tetrahydrofuran solution of 1.75 g of 4,6-dichloro-5-fluoropyrimidine, and stirred for 90 minutes at 0° C. The reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 1.8 g of 4-(2-butynyloxy)-6-chloro-5-fluoropyrimidine.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:23])[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9](B3OC(C)(C)C(C)(C)O3)[CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:31]1[CH:45]=[CH:44][C:34]2[C:35]([CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)=[N:36][O:37][C:33]=2[CH:32]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[CH:1]1([CH2:4][NH:5][C:6](=[O:23])[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:31]3[CH:45]=[CH:44][C:34]4[C:35]([CH:38]5[CH2:39][CH2:40][NH:41][CH2:42][CH2:43]5)=[N:36][O:37][C:33]=4[CH:32]=3)[CH:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc2c(C3CCNCC3)noc2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1ccc2c(C3CCNCC3)noc2c1
Yield: 50.3 %

Procedure:
N-Cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 21, 100 mg), DME (5 ml), aqueous sodium carbonate (1M, 3 ml), tetrakis (triphenylphosphine) palladium (0) (37 mg) and 6-bromo-3-piperidin-4-yl-1,2-benzisoxazole (76 mg) were heated together at 80° C. under nitrogen for 18 h. The solvent was evaporated and the residue was purified by column chromatography on silica (10 g ) eluting with dichloromethane:ethanol:ammonia (100:8:1 to 70:8:1) to give the title compound (53 mg).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13](/[CH:16]=[CH:17]/[C:18]([O:20]CC4C=CC=CC=4)=[O:19])[CH:14]=3)[N:9]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:8]=2[CH3:34])[CH:5]=[CH:4][N:3]=[CH:2]1>O1CCCC1.[Pd]>[C:18]([CH2:17][CH2:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:8]([CH3:34])=[C:7]2[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([OH:20])=[O:19]
Reactant: COC(=O)CCn1c(C)c(Cn2ccnc2)c2cc(/C=C/C(=O)OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)CCn1c(C)c(Cn2ccnc2)c2cc(CCC(=O)O)ccc21

Procedure:
A solution of benzyl (E)-3-[3-(1H-imidazol-1-ylmethyl)-1-(2-methoxycarbonylethyl)-2-methyl-1H-indol-5-yl]-2-propenoate (2.0 g) in tetrahydrofuran (40 ml) was hydrogenatedat room temperature and 4.5 atm. in the presence of 10% palladium on carbon(0.20 g) until reaction was complete (5 hours). The mixture was filtered and the residue was washed with ethyl acetate. The combined filtrate and washings were evaporated and the residue was triturated with ether to givethe title compound (1.52 g), m.p. 134°-137° C. Found: C,65.31; H,6.35; N,10.70. C20H23N3O4 requires: C,65.02; H,6.28N,11.38%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=1.[CH2:17]([C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=2)[N:21]([NH2:32])[CH:20]=1)[CH3:18].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[CH2:17]([C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]([F:29])([F:31])[F:30])[CH:26]=2)[N:21]([NH:32][C:14]([C:10]2[C:11]([CH3:13])=[N:12][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][CH:9]=2)=[O:16])[CH:20]=1)[CH3:18]
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Reactant: CCc1cn(N)c2ccc(C(F)(F)F)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCc1cn(NC(=O)c2cnc(-c3ccccn3)nc2C)c2ccc(C(F)(F)F)cc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
A solution of 2-(2-pyridyl)-4-methyl-pyrimidine-5-carboxylic acid (215 mg, 1 mmol) and 3-ethyl-5-trifluoromethyl-indol-1-ylamine (228 mg, 1 mmol) in DMF (5 mL) is stirred at 50° C. for 1 h. The mixture is treated with DMTMM (276 mg, 1 mmol) and stirred at 50° C. for 2 h. The mixture is diluted with saturated aqueous Na2CO3 (5 mL) and stirred for 5 min. The precipitate is collected by filtration and dried in vacuo to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (3-ethyl-5-trifluoromethyl-indol-1-yl)-amide (235 mg, 55%). MS: 426 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.28 (s, 1H), 8.81 (d, 1H), 8.48 (d, 1H), 8.03 (m, 1H), 7.99 (s, 1H), 7.60 (m, 4H), 2.82 (q, 2H), 2.79 (s, 3H), 1.31 (t, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C[Mg]Br.[CH2:15]=[O:16].Cl>O1CCCC1.C(OCC)C.C(N(CC)CC)C.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:15]=[O:16])[C:6]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=O
Reactant: CC(C)(C)c1ccccc1O
Agent: C[Mg]Br
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(C=O)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To 50 mmol of 2-tert-butyl phenol in 40 ml of tetrahydrofuran was added dropwise a 3-molar methylmagnesium bromide solution (18.5 ml; 55.5 mmol) in diethyl ether. After two hours of stirring at room temperature, gas evolution ceased. About 90% of the solvent were removed in vacuo and toluene (100 ml), triethylamine (10 ml), and paraformaldehyde (3.75 g; 125 mmol) were added. The mixture was heated to 88° C. and held at this temperature for two hours. After cooling down to room temperature, the yellow solution was introduced into cold hydrochloric acid (1M, 250 ml). The organic phase was separated and dried over sodium sulphate. After removal of the solvent in vacuo, 3-tert-butyl salicylaldehyde was purified by high vacuum distillation. Yield: 88%.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1>>[C:19]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:20]=[CH:21][C:22]([CH2:25][C:26]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:27])=[CH:23][CH:24]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1ccc(-c2ccccc2)cc1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(biphenyl-4-yl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.32 (d, J=7.9 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.89-7.93 (m, 1H), 7.56-7.69 (m, 4H), 7.47-7.50 (m, 4H), 7.38 (t, J=7.4 Hz, 1H), 3.78-3.84 (m, 4H), 3.72 (s, 2H), 3.09-3.11 (m, 4H); MS (ESI+) M/Z 441 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([F:29])[CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:32]1([CH2:37][CH2:38][C:39](Cl)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][N:18]([C:39](=[O:40])[CH2:38][CH2:37][CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([F:29])[CH:20]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(C(=O)OC)c(F)c3)cc2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)c3ccc(C(=O)OC)c(F)c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure B using methyl 4-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate and 3-cyclopentylpropionyl chloride as a pale yellow oil (54%). M+ (ESI): 540.1. HPLC, Rt: 6.35 min (Purity: 98.2%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]([O:19][CH3:20])=[O:18])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(C(C)C)CC)(C)C.[N:30]1([CH2:35][CH2:36][O:37][CH2:38][CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1.O>[C:11]1([C:10]2[C:3]3[C:2]([N:42]4[CH2:43][CH2:44][CH:39]([CH2:38][O:37][CH2:36][CH2:35][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:40][CH2:41]4)=[N:7][CH:6]=[N:5][C:4]=3[S:8][C:9]=2[C:17]([O:19][CH3:20])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1-c1ccccc1
Reactant: C1CCN(CCOCC2CCNCC2)C1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1sc2ncnc(N3CCC(COCCN4CCCC4)CC3)c2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a stirred solution of methyl 4-chloro-5-phenyl-thieno[2,3-d]pyrimidine-6-carboxylate (0.850 g, 2.80 mmol) in THF (50 mL), was added diisopropylethylamine (0.73 mL, 4.20 mmol) and 4-(2-pyrrolidin-1-ylethoxymethyl)piperidine (0.890 g, 4.20 mmol) in one portion, and the reaction left to stir at room temperature for 2 hours. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The reaction was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography using DCM: MeOH (0-25%) as eluent to afford the named product (1.012 g, 75%). m/z [M+H]+481; RT=3.03 min.
Reaction SMILES: [OH-].[K+].[CH3:3]I.[Cl:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:13]([C:15]3[C:19]4=[N:20][C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=[C:18]4[NH:17][CH:16]=3)=[CH:14][C:7]=12>CN(C=O)C.CCOC(C)=O>[Cl:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:29])=[O:30])[C:13]([C:15]3[C:19]4=[N:20][C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=[C:18]4[N:17]([CH3:3])[CH:16]=3)=[CH:14][C:7]=12
Reactant: CI
Reactant: COc1cc2[nH]cc(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)c2nc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reaction time: 1.5 h
Yield: 104.3 %

Procedure:
Add KOH (5.0 equiv., 21.6 mg) then MeI (5.0 equiv., 55.0 mg, 24 μL) to bisazaindole 28 (37.3 mg, 0.0772 mmol) stirred in DMF (5.0 mL) at 0° C., and stir the reaction medium at for 1.5 h. Then allow the reaction medium to return to room temperature, dilute it with EtOAc, wash it with saturated NaHCO3, dry (MgSO4) and concentrate, to obtain 29 (40 mg, 100%) as an amorphous solid: TLC (EtOAc at 40%/heptane) Rf=0.10.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[C@@H:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:2]2.C(N(CC)CC)C.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:2]2[C@H:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C@@H:4]3[CH2:7][C@H:1]2[CH2:6][CH2:5]3)(=[O:30])=[O:29])=[CH:26][CH:27]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)[C@H]1N[C@@H]2CC[C@H]1C2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)N1S(=O)(=O)c1ccc(OC)cc1
Yield: 71.6 %

Procedure:
To a solution of ethyl (1R, 3S, 4S)-2-azabicyclo[2.2.1]heptane-3-carboxylate (0.724 g, 4.28 mmol) in chloroform (8 ml) was added triethylamine (0.60 ml, 4.28 mmol) and 4-methoxybenzenesulfonyl chloride (0.973 g, 4.71 mmol) while being cooled with ice. After a reaction at room temperature for 4 hours, the reaction mixture was washed with 1N hydrochloric acid, saturated sodium bicarbonate water and saturated brine successively, and dried over magnesium sulfate. The solvent was evaporated and the residue was recrystallized (hexane/ethyl acetate), to give ethyl (1R, 3S, 4S)-2-[(4-methoxyphenyl)sulfonyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate (1.04 g, 71%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([NH:8][CH3:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl.[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18]Cl>C1COCC1>[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][N:8]([CH3:9])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1
Reactant: CN(C)CCCl
Reactant: CNc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCN(C)c1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 55.1 %

Procedure:
To a solution containing 1.52 g of 4-nitro-N-methylaniline (10 mmol) in 30 mL THF, was added 0.8 g of sodium hydride (60% dispension in oil, 20 mmol). After 5 minutes at room temperature, 2.59 g of 2-(dimethylamino)ethyl chloride hydrochloride (18 mmol) and 0.4 g of sodium hydride (60% dispension in oil, 10 mmol) were added. The reaction was heated at 60° C. for 5 hours. The solvent was concentrated in vacuo to yield a residue which was partitioned between ethyl acetate and 2 M sodium hydroxide solution. The organic phase was washed with water (3×), dried over anhydrous sodium sulphate, filtered, and concentrated in vacuo to yield the title compound as a brown oil (1.23 g, 55%). MS (ES+) m/e 224 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[CH:26][CH:27]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)cc2)CC1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (73.0 mg, 0.286 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (29.0 mg, 0.0530 mmol) as the ligand in a manner analogous to Step 2d. The reaction product was isolated as pale yellow solid (0.022 g, 18%). MP=242-244° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (dd, J=6.7, 1.1 Hz, 1H), 8.25-8.20 (m, 2H), 8.10-8.06 (m, 2H), 7.63 (dd, J=7.4, 1.1 Hz, 1H), 7.51-7.46 (m, 2H), 7.01-6.95 (m, 2H), 6.67 (s, 1H), 3.20-3.15 (m, 4H), 3.10 (s, 3H), 2.62-2.58 (m, 4H), 2.36 (s, 3H). MS=463 (MH)+.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.CC(C)(C)C(=O)CN1C2C=CC=CC=2C(C2C=CC=CC=2)=NN(CC(O)=O)C1=O.[C:69]([O:73][C:74](=[O:84])[N:75](C1C=CC=C(N)C=1)[CH3:76])([CH3:72])([CH3:71])[CH3:70].C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[C:69]([O:73][C:74](=[O:84])[N:75]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:17]3[CH2:16][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])[C:14]2=[O:37])[CH:5]=1)[CH3:76])([CH3:72])([CH3:71])[CH3:70]
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(N)c1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(c2ccccc2)c2ccccc21
Agent: COC(=O)c1cccc(N)c1
Product: CN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1, step e) except that [1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-5-phenyl-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 4, step a) and (3-amino-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step c) were used in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step d), according to the method of Example 3, step e. 1H NMR (CDCl3) 8.01 (1H, s), 7.63 (2H, m), 7.55 (1H, m), 7.42 (3H, m), 7.25 (2H, m), 7.14 (1H, d), 7.00 (1H, t), 6.90 (1H, t), 6.40 (1H, dd), 6.29 (1H, dd), 4.76 (2H, m), 4.52 (1H, d), 4.34 (1H, d), 3.25 (1H, br s), 2.77 (3H, s), 1.26 (9H, s). Found: C, 68.44; H, 6.46; N, 13.80%; C29H31N5O3.0.6H2O requires: C, 68.41; H, 6.39; N, 13.76%.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:7]=[CH:6][C:5]=1[OH:18])[CH:2]=[CH2:3].[OH-].[K+]>CO>[CH:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:7]=[CH:6][C:5]=1[OH:18])=[CH:2][CH3:3]
Reactant: C=CCc1cc(Oc2ccccc2Cl)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC=Cc1cc(Oc2ccccc2Cl)ccc1O
Yield: 100 %

Procedure:
A mixture of 2-allyl-4-(2-chlorophenoxy)phenol (14.5 g) and potassium hydroxide (20 g) in methanol (70 ml) was treated in a similar manner to that of Example 4-(2) to give oily 2-(1-propenyl)-4-(2-chlorophenoxy)phenol (14.5 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>CN(C)C=O>[N:29]1([CH2:28][CH2:27][CH2:26][NH:25][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:12])[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: NCCCn1ccnc1
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(NCCCn1ccnc1)c1n[nH]c2ccccc12
Temperature: 60 °C

Procedure:
Indazole-3-carboxylic acid (810 mg, 5 mmol) is heated at 60° C. in the presence of carbonyldiimidazole (891 mg, 5.5 mmol) in N,N-dimethylformamide (DMF) (14 ml) under argon for 3 h. 1-(3-Aminopropyl)-imidazole (597 μl, 5 mmol) in solution in DMF (2 ml) is added and the mixture is heated for 2 h and 20 min at 60° C. After cooling, the DMF is evaporated under vacuum to give a yellow oil which is chromatographed on 54 g of silica. The compound obtained is eluted with an ethyl acetate (AcOEt)/methanol (MeOH) (9/1) mixture.