Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][C:33]2[CH:34]=[N:35][C:36]([O:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:37][CH:38]=2)=[CH:27][CH:26]=1)([CH3:24])[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:31]([C:28]1[CH:27]=[CH:26][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:30][CH:29]=1)[CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:37][CH:38]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(NCc2ccc(Oc3ccccc3)nc2)cc1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Product: CC(C)c1ccc(N(Cc2ccc(Oc3ccccc3)nc2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 48.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.42 g) and (4-isopropylphenyl)[(6-phenoxypyridin-3-yl)methyl]amine (0.47 g) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-[(6-phenoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.42 g) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][CH:24]=[CH:25][C:26](OCC)=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][CH:24]=[CH:25][CH2:26][OH:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=CCOC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCC=CCO)N(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 10 h
Yield: 56 %

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-[{3-(ethoxycarbonyl)-2-propenyl}oxymethyl]-4-methanesulfonyloxypyrrolidine (10 g) in tetrahydrofuran (120 ml) was added dropwise 1.0 M solution of diisobutylaluminum hydride in toluene (56.6 ml) at -40° C. and the mixture was allowed to warm to 0° C. and stirred for 10 hours at the same temperature. The reaction mixture was added dropwise 1N hydrochloric acid (50 ml), and the resulting precipitate was filtered off. The filtrate was dissolved in a mixture of ethyl acetate (200 ml) and water (100 ml). The organic layer was separated, washed with brine (100 ml), dried over magnesium sulfate and treated with active carbon. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (200 ml) eluting with a mixture of hexane and ethyl acetate (1:4 V/V) to give (2S,4R)-1-benzyloxycarbonyl-2-(4-hydroxy-2-butenyl)oxymethyl-4-methanesulfonyloxypyrrolidine (5.07 g).
Reaction SMILES: [CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18](/[CH:21]=[CH:22]/[C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH2:32][C@H:33]4[CH2:37][O:36]C(C)(C)[O:34]4)[CH:27]=[CH:26]5)(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].O>C(Cl)Cl.CO>[CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18](/[CH:21]=[CH:22]/[C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH2:32][C@H:33]([OH:34])[CH2:37][OH:36])[CH:27]=[CH:26]5)(=[O:19])=[O:20])[CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC[C@H](Cn2ccc3cc(/C=C/S(=O)(=O)N4CCC5(CC4)N=C(C4CCCCC4)NC5=O)ccc32)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: O=C1NC(C2CCCCC2)=NC12CCN(S(=O)(=O)/C=C/c1ccc3c(ccn3C[C@H](O)CO)c1)CC2
Reaction time: 48 h
Yield: 86 %

Procedure:
2-Cyclohexyl-8-{(E)-2-[1-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-indol-5-yl]-ethenesulfonyl}-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (41.9 mg, 0.0755 mmol) was dissolved in a methylene chloride-methanol mixed solution (1:1, 1.5 ml). Trifluoroacetic acid (0.35 ml) was added and the mixture was stirred for two days. A saturated aqueous sodium bicarbonate solution and water were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by P-TLC (ethyl acetate-methanol) to give 2-cyclohexyl-8-{(E)-2-[1-((S)-2,3-dihydroxy-propyl)-1H-indol-5-yl]-ethenesulfonyl}-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (33.4 mg, 86%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([CH2:26][CH2:27][C:28]([OH:30])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:39]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[N:11]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][C:16]([CH2:26][CH2:27][C:28]([NH2:39])=[O:30])=[CH:15][CH:14]=2)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CCC(=O)O)ccc2c1=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CCC(N)=O)ccc2c1=O
Yield: 92.7 %

Procedure:
A solution of 3-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)propanoic acid (0.33 g, 0.7 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.27 g, 1.4 mmol) and 1-hydroxybenzotriazole ammonium salt (0.21 g, 1.4 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The resulting reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[6-(3-amino-3-oxopropyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.31 g, 93.9%) as crystals.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O.[Cl:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][C:21]([NH:23][C@H:24]2[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]2)=O)[CH:16]=[CH:17][CH:18]=1>C1COCC1>[Cl:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][NH:23][C@H:24]2[CH2:25][CH2:26][C@H:27]([CH3:30])[CH2:28][CH2:29]2)[CH:16]=[CH:17][CH:18]=1
Reactant: C[C@H]1CC[C@H](NC(=O)CCc2cccc(Cl)c2)CC1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](NCCCc2cccc(Cl)c2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1M Lithium aluminium hydride (5 mL, 5 mmol) and dry THF (5 mL) was cooled to 0° C. where upon 98% sulphuric acid (133 μL, 2.5 mmol) was added over a period of 10 min. The resulting solution was stirred for 10 min at 0° C. and then allowed to warm to room temperature over 30 min. 3-(3-Chloro-phenyl)-N-(trans-4-methyl-cyclohexyl)-propionamide (900 mg, 3.2 mmol) in THF (6 mL) was added and the solution stirred for 16 h at room temperature. The reaction was quenched by the sequential addition of water (190 μL), 4N NaOH (190 μL) and water (190 μL). Dilution with THF (25 mL) followed by the addition of MgSO4 (5 g), filtration and concentration in vacuo yielded 700 mg of [3-(3-Chloro-phenyl)-propyl]-(trans-4-methyl-cyclohexyl)-amine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:24]4[O:23][CH2:22][CH2:21][N:20]([CH:25]5[CH2:28][N:27]([C:29](OC(C)(C)C)=[O:30])[CH2:26]5)[CH2:19][C:18]=4[C:17]([CH3:36])=[C:16]([Cl:37])[CH:15]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.Cl.[CH:39](N(CC)C(C)C)(C)C.C(OC(=O)C)(=O)C>O1CCOCC1.CN(C)C=O.CO>[C:29]([N:27]1[CH2:26][CH:25]([N:20]2[CH2:19][C:18]3[C:17]([CH3:36])=[C:16]([Cl:37])[CH:15]=[C:14]([CH:12]([N:8]4[C:4]5=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]5[C:10]([CH3:11])=[N:9]4)[CH3:13])[C:24]=3[O:23][CH2:22][CH2:21]2)[CH2:28]1)(=[O:30])[CH3:39]
Reactant: Cc1c(Cl)cc(C(C)n2nc(C)c3c(N)ncnc32)c2c1CN(C1CN(C(=O)OC(C)(C)C)C1)CCO2
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CC(N2CCOc3c(C(C)n4nc(C)c5c(N)ncnc54)cc(Cl)c(C)c3C2)C1
Reaction time: 0.08 h
Yield: 13.4 %

Procedure:
tert-Butyl 3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxylate (15 mg, 0.035 mmol) was treated with 4 N HCl in dioxane (1 mL), and then the solvent was evaporated. The residue was stirred in N,N-dimethylformamide (0.5 mL) with N,N-diisopropylethylamine (10 μL, 0.06 mmol) and acetic anhydride (20 μL, 0.2 mmol) was added. The mixture was stirred for 5 minutes and diluted with methanol. Purification by preparative LCMS (pH 10) gave the desired compound (2.2 mg, 13%). LCMS calculated for C23H29ClN7O2 (M+H)+: m/z=470.2; found: 470.2. 1H NMR (300 MHz, CD3OD): δ 8.14 (s, 1 H), 7.33 (s, 1 H), 6.33 (m, 1 H), 4.27 (m, 1 H), 4.02 (m, 2 H), 3.80 (m, 1 H), 3.72 (m, 1 H), 3.69 (m, 3 H), 3.48 (m, 1 H), 2.79 (m, 2 H), 2.58 (s, 3 H), 2.38 (s, 3 H), 1.82 (m, 3 H), 1.77 (m, 3 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15].CC1(C)C(C)(C)OB([C:24]2[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=2)O1.[F-].[K+].CC#N>C(Cl)Cl.O.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>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:24]2[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=2)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15]
Reactant: CC1(C)OB(c2ccc(C=O)cc2)OC1(C)C
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1nc(-c2ccc(C=O)cc2)c(F)c(N)c1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.6 %

Procedure:
To a 5-mL microwave safe vial was added methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate (0.400 g, 1.705 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (0.435 g, 1.875 mmol), KF (0.297 g, 5.11 mmol), and PdCl2(PPh3)2 (0.120 g, 0.170 mmol). A mixture of H2O (1 mL) and CH3CN (2 mL) was added, and the reaction vial was capped and placed in a Biotage Initiator microwave reactor for 20 min at 115° C. with external IR-sensor temperature monitoring from the side of the vessel. Upon cooling to room temperature, the reaction mixture was diluted with CH2Cl2 (25 mL) and H2O (25 mL), and the organic layer was filtered through a cotton plug. An additional extraction using EtOAc (25 mL) was combined with the CH2Cl2 and dried over Na2SO4 (50 g). Following filtration of the combined organics through a cotton plug and concentration on a rotary evaporator, the residue was purified using a Teledyne ISCO purification system with a gradient eluent system of CH2Cl2 and EtOAc to yield the title compound as a tan solid (335 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.09 (dd, J=8.3, 1.5 Hz, 2H), 8.03-7.93 (m, 2H), 4.62 (s, 2H), 4.00 (s, 3H), 3.98 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −139.69; ESIMS m/z 305 ([M+H]+), 303 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C([N-]C(C)C)(C)C.[Li+].[C:19](#[N:28])[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.O>O1CCCC1.O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([C:19]2[N:28]=[C:4]([OH:6])[C:3]3[CH:7]=[CH:8][CH:9]=[N:10][C:2]=3[CH:1]=2)=[CH:21][CH:22]=1)#[N:25]
Reactant: Cc1ncccc1C(=O)O
Reactant: N#Cc1ccc(C#N)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2cc3ncccc3c(O)n2)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
1 g 2-methyl-nicotinic acid was suspended in 30 mL of tetrahydrofuran and cooled to −78° C. under nitrogen before 14.6 mL lithium diisopropylamide (as a 2.0 M in tetrahydrofuran/n-heptane/ethylbenzene) was added dropwise and the mixture was stirred for 2 h at −78° C. and then warmed to ambient temperature where it was maintained for a further 2 h. After this time the mixture was cooled to −78° C. and it was added dropwise into a solution of 1.87 g terephthalonitrile (4.33) in 30 mL tetrahydrofuran. The reaction mixture was stirred for 2 h and then warmed to ambient temperature overnight. After this time 20 mL water was added and the solvent was removed under reduced pressure before 20 mL ethyl acetate was introduced and the precipitate that was formed was collected by filtration. The solid material that was collected (title compound) was used without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][CH2:4][Mg]Cl.[CH2:9]([O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15](Br)[CH:14]=1)[CH3:10]>O1CCOCC1.C(OCC)C.[Cl-].[Cl-].[Zn+2].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]>[CH2:9]([O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH2:4][CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])[CH:14]=1)[CH3:10]
Reactant: CCOC(=O)c1ccc(Cl)c(Br)c1
Reactant: CC(C)(C)CC[Mg]Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOC(=O)c1ccc(Cl)c(CCC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3,3-dimethyl-1-butylmagnesium chloride (8.00 mmol, 0.5 M THF, Platte Valley Scientific) was added dropwise to a solution of ZnCl2 (4.00 mmol, IM diethyl ether, Aldrich) in 1,4-dioxane (15 mL) at ambient temperature. The mixture was stirred 30 minutes followed by addition of 3-bromo-4-chlorobenzoic acid ethyl ester (1.05 g, 3.99 mmol) and Pd(dppf)2Cl2 (131 mg, 0.160 mmol). The mixture was heated to reflux for 30 minutes, cooled to ambient temperature, diluted with diethyl ether and quenched with H2O. The mixture was filtered through celite and the filtrate was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. Flash chromatography eluting with 5% to 15% ethyl acetate/hexanes provided the title compound. 1H NMR (DMSO-d6) δ 7.89 (d, 1H), 7.78 (dd, 1H), 7.56 (d, 1H), 4.32 (q, 2H), 2.73 (m, 2H), 1.41 (m, 2H), 1.32 (t, 3H), 0.97 (s, 9H); MS (DCI+) m/z 286 (M+NH4)+, 269 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[C:16]1([CH2:22][CH2:23][C:24]#[CH:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C=O)C.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.[Cu]I>[CH:11]1([NH:10][C:3]2[C:2]([C:25]#[C:24][CH2:23][CH2:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7][N:6]=[C:5]([C:8]#[N:9])[N:4]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C#CCCc1ccccc1
Reactant: N#Cc1ncc(Br)c(NC2CCCC2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ncc(C#CCCc2ccccc2)c(NC2CCCC2)n1
Yield: 89.9 %

Procedure:
5-Bromo-4-cyclopentylamino-pyrimidine-2-carbonitrile (0.69 mmol), 4-phenyl-1-butyne (1.66 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.035 mmol), copper (I) iodide (0.07 mmol) and triethylamine (2.1 mmol) in DMF (5 ml) is stirred at 75° C. for 2.5 h. The reaction mixture is treated with saturated ammonium chloride and extracted with AcOEt. The organic layer is washed with brine, dried over magnesium sulfate and evaporated down. The crude product is applied to a silica gel column chromatography, which is eluted with following solvents: n-hexane:AcOEt=12:1 (v/v) and n-hexane:AcOEt=10:1 (v/v). The solvent of the latter effluent is removed by evaporation and dried in vacuo to afford the title compound. yield 89.9%, Rf=0.65 (n-hexane:AcOEt=2:1).
Reaction SMILES: [CH3:1][C:2]1[C:7](Br)=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH3:11].C([Li])CCC.[B:17](OC)([O:20]C)[O:18]C.Cl>C1COCC1>[CH3:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][CH:5]=[C:6]([CH3:9])[C:7]=1[B:17]([OH:20])[OH:18]
Reactant: COB(OC)OC
Reactant: COc1ccc(C)c(Br)c1C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C)c(B(O)O)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,4-dimethyl-3-bromoanisole (3.3 g, 15 mmol) in THF (15 mL) is added dropwise at −78° C. to a solution of n-butyllithium (11 mL of 1.6M in hexane, 17 mmol) in THF (35 mL). After 30 min, trimethyl borate (2.3 mL, 20 mmol) is added and the mixture is allowed to warm to room temperature overnight. The mixture is poured onto 10% HCl and extracted with EtOAc. The organic fraction is washed with saturated brine, dried (Na2SO4), and concentrated to give the desired product as a brownish oil. 1H NMR (CDCl3) 6.98 (d, 1H), 6.75 (d, 1H), 4.64 (br s), 3.80 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: C([Li])CCC.[CH2:6]([C:12]1[C:17]([CH2:18][CH2:19][CH3:20])=[C:16]([CH2:21][CH2:22][CH3:23])[C:15]([CH2:24][CH2:25][CH3:26])=[C:14]([CH2:27][CH2:28][CH3:29])[C:13]=1[CH2:30][C:31]#[C:32][CH2:33][CH2:34][CH3:35])[C:7]#[C:8][CH2:9][CH2:10][CH3:11].I[C:37]1[CH:42]=[CH:41][C:40](I)=[C:39]([I:44])[C:38]=1[I:45].CN1C(=O)N(C)CCC1.Cl>Cl[Cu].C1COCC1>[I:44][C:39]1[C:38]([I:45])=[CH:37][C:42]2[C:41](=[C:8]([CH2:9][CH2:10][CH3:11])[C:7]3[CH2:6][C:12]4[C:13]([CH2:30][C:31]=3[C:32]=2[CH2:33][CH2:34][CH3:35])=[C:14]([CH2:27][CH2:28][CH3:29])[C:15]([CH2:24][CH2:25][CH3:26])=[C:16]([CH2:21][CH2:22][CH3:23])[C:17]=4[CH2:18][CH2:19][CH3:20])[CH:40]=1
Reactant: CCCC#CCc1c(CC#CCCC)c(CCC)c(CCC)c(CCC)c1CCC
Reactant: Ic1ccc(I)c(I)c1I
Agent: Cl[Cu]
Agent: Cl
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCCc1c(CCC)c(CCC)c2c(c1CCC)Cc1c(c(CCC)c3cc(I)c(I)cc3c1CCC)C2
Yield: 32.5 %

Procedure:
n-Butyl lithium (3.0 ml, 4.8 mmols, 1.6mol/l) was added to a THF solution (20 ml) of Cp2ZrCl2 (0.702 g, 2.4 mmols) at −78° C. After the mixture was stirred for an hour, 1,2-bis(2-hexynyl)-3,4,5,6-tetrapropylbenzene (0.813 g, 2.0 mmols) was added to the mixture. A cooling bath was withdrawn, and the mixture was stirred for an hour. Tetraiodobenzene (1.16 g, 2.0 mmols), DMPU (0.73 ml, 6.0 mmols) and CuCl (0.416 g, 4.2 mmols) were added to the mixture. After stirring for an hour at 50° C., 3N HCl was added to terminate the reaction. The reaction mixture was extracted with chloroform. The extract was then washed with sodium hydrogencarbonate aqueous solution and brine. After the pressure was reduced, column chromatography was performed using silica gel as the packing material to give the title compound (0.477 g) as a pink solid. The isolation yield was 33%
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:17]2[CH:26]=[CH:27][C:28]([S:30]([N:33]3[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34]3)(=[O:32])=[O:31])=[CH:29][C:16]=2[N:15]=1)([CH3:13])([CH3:12])[CH3:11].[CH2:41]([NH2:44])[CH:42]=[CH2:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:41]([NH:44][C:38]([C:35]1[CH:36]=[CH:37][N:33]([S:30]([C:28]2[CH:27]=[CH:26][C:17]3[N:18]([CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]([C:10]([CH3:12])([CH3:11])[CH3:13])=[N:15][C:16]=3[CH:29]=2)(=[O:32])=[O:31])[CH:34]=1)=[O:39])[CH:42]=[CH2:43]
Reactant: C=CCN
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCNC(=O)c1ccn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)c1

Procedure:
Following the same procedure in Example 33, step A, using DIPEA (0.1 mL, 74 mg, 0.57 mmol), 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carboxylic acid (0.078 mmol) (see the step B in example 33 for preparation), allylamine (0.1 mL, 76 mg, 1.33 mmol) and HATU (100 mg, 0.31 mmol) in DMF (5 mL). The crude product was purified by MPLC using Hex/EtOAc (3:7) on silica gel to 32 mg (85%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.41-1.57 (m, 4 H), 1.60 (s, 9 H), 2.20-2.41 (m, 1 H), 3.24-3.38 (m, 2 H), 3.84-3.97 (m, 4 H), 4.43 (d, J=7.42 Hz, 2 H), 5.03-5.10 (m, 1 H), 5.10-5.19 (m, 1 H), 5.75-5.94 (m, 1 H), 6.67 (dd, J=3.32, 1.76 Hz, 1 H), 7.30 (dd, J=3.42, 2.25 Hz, 1 H), 7.79-7.85 (m, 1 H), 7.93 (d, J=9.0 Hz, 1H), 7.970 (dd, dd=9.0, 1.8 Hz, 1 H), 8.27 (d, J=1.76 Hz, 1 H); MS (ESI) (M+H)+=484.7; Anal. Calcd for C25H32N4O4S+0.90 TFA+0.20H2O (590.85): C, 54.48; H, 5.68; N, 9.48. Found: C, 54.53; H, 5.69; N, 9.57.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:68]([SH:75])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1.C(N(C(C)C)CC)(C)C>C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].O1CCOCC1>[CH2:68]([S:75][C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1)[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1
Reactant: SCc1ccccc1
Reactant: CN1CCC(OC(c2cccc(Br)c2)c2nc3ccccc3s2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(OC(c2cccc(SCc3ccccc3)c2)c2nc3ccccc3s2)CC1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
A screw-cap tube is charged with 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (208 mg), palladium bis(dibenzylideneacetone) (14 mg), Xantphos (14 mg), benzyl mercaptan (59 μL), diisopropylethylamine (174 μL) and 1,4-dioxane (2 mL). The tube is evacuated, filled with argon and sealed. After stirring at 120° C. for 15 h, the mixture is diluted with ethyl acetate and water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 100/0/0 to 95/5/0.5). The residual yellowish oil is re-crystallized from hot acetonitrile to give 2-[(3-benzylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole melting at 195° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2F)[N:5]=[CH:4][C:3]=1[C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=O)[CH:17]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.Cl.C(OCC)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:17]=1
Reactant: C1CCNCC1
Reactant: Nc1c(C(=O)c2cccc(C=O)c2)cnn1-c1ccc(F)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Nc1c(C(=O)c2cccc(CN3CCCCC3)c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.6 %

Procedure:
To a solution of 5-amino-1-(2,4-difluorophenyl)-4-[3-formylbenzoyl] pyrazole (0.3 g, 0.92 mmol), piperidine (0.1 ml, 1.0 mmol), acetic acid (0.05 ml) in 1,2-dichloroethane (5 ml) was added sodium triacetoxyborohydride (0.29 g, 1.37 mmol). After stirring at room temperature for 12 hours, the reaction was diluted with 10% hydrochloric acid and ethyl acetate (10 ml). The aqueous layer was separated and neutralized to pH 9 with sodium hydroxide and was then extracted with ethyl acetate. The combined organics were separated and washed with brine (25 ml), dried over MgSO4 and then concentrated in vacuo to a brown oil. The oil was purified by flash column chromatography using 1:1 hexanes/ethyl acetate to remove impurities and ethyl acetate to elute the desired product. Concentration of the column fractions in vacuo gave 5-amino-1-(4-fluorophenyl)-4-[3-(1-piperidinylmethyl)benzoyl] pyrazole as an oil (0.211 g). The compound was triturated to a solid from hexanes/ethyl acetate.