Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])[CH2:34][CH2:33]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Product: COc1ccccc1N1CCN(C(=O)Nc2nc(C)c(C)nc2OC)CC1
Yield: 82 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[C:9]([O:13][C:14](=[O:21])[NH:15][C@@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][C:14](=[O:21])[NH:15][C@@H:16]1[CH2:20][CH2:19][N:18]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:17]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: Fc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(Br)cn2)C1
Yield: 30.9 %

Procedure:
Prepare the title compound by essentially following the procedure as described for Preparation 49, using 5-bromo-2-fluoro-pyridine (6.26 g, 35.61 mmol), and (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (6.632 g, 35.61 mmol) to give 3.77 g (30%) of the title compound. LC-MS/ES m/z (81Br) 344.3 [M+H]+.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:11]=[C:12]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=2[OH:22])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.OC1[CH2:33][C:32]([CH3:35])([CH3:34])[N:31]([O:36][CH3:37])[C:30]([CH3:39])([CH3:38])[CH2:29]1>C1(C)C(C)=CC=CC=1>[N:1]1[N:2]([C:10]2[CH:11]=[C:12]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=2[OH:22])[CH2:13][CH2:14][C:15]([O:17][CH:18]2[CH2:35][C:32]([CH3:34])([CH3:33])[N:31]([O:36][CH3:37])[C:30]([CH3:39])([CH3:38])[CH2:29]2)=[O:16])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: COC(=O)CCc1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)C)c1
Reactant: CON1C(C)(C)CC(O)CC1(C)C
Solvent: Cc1ccccc1C
Product: CON1C(C)(C)CC(OC(=O)CCc2cc(-n3nc4ccccc4n3)c(O)c(C(C)(C)C)c2)CC1(C)C
Temperature: 100 °C
Yield: 56.7 %

Procedure:
A mixture of 30.0 grams (84.9 mmol) of methyl 3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyhydrocinnamate, 19.1 grams (102 mmol) of 4-hydroxy-1-methoxy-2,2,6,6-tetramethylpiperidine, and 200 ml of xylene is heated at reflux in a round-bottomed flask equipped with a fractionating column and an adjustable still head. Approximately 25 ml of wet xylene is distilled from the reaction mixture. The reaction mixture is then cooled to 100° C., treated with 1.4 gram of lithium amide, and diluted with 100 ml of xylene. The mixture is heated at reflux for sixteen hours while methanol is removed by fractional distillation. The reaction mixture is diluted with 200 ml of toluene, and washed successively with 1N hydrochloric acid (200 ml) and saturated sodium bicarbonate solution (300 ml). Solids are removed by filtration, and the filtrate is dried over anhydrous magnesium sulfate and then concentrated to obtain a brown solid. The crude product is passed through a layer of silica gel (2:1 heptane:ethyl acetate). The eluent is evaporated to give a solid which is recrystallized from isopropanol to afford 24.5 grams (57% yield) of the title compound as a white solid melting at 135°-137° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][C@@H:20]([CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][C@@H:20]([CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)[C@@H](N)Cc1cccc2ccccc12
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-3-(1-naphthyl)propionate hydrochloride (Bachem), the title compound was prepared as a solid (mp=103-130° C.). The reaction was monitored by tlc (Rf=0.8 in 5% MeOH/methylene chloride) and the product was purified by flash column chromatography using 6% MeOH/methylene chloride as the eluent.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[F:28][C:29]([F:43])([C:39]([F:42])([F:41])[F:40])[CH2:30]OS(C(F)(F)F)(=O)=O>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])(=[O:17])=[O:16])[CH2:12][N:11]2[CH2:30][C:29]([F:43])([F:28])[C:39]([F:42])([F:41])[F:40])=[O:9])[CH2:5][CH2:6]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2)CC1
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2CC(F)(F)C(F)(F)F)CC1

Procedure:
(2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K5 was reductively aminated with 2,2,3,3,3-pentafluoropropyltrifluoromethane sulfonate in analogy to experiment L3 to give (2S,4R)-1-(2,2,3,3,3-pentafluoro-propyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a pale brown oil. MS: 520.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([CH3:12])([OH:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.[CH3:15][C:16]([CH3:18])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2([CH3:12])[CH2:9][O:10][C:16]([CH3:18])([CH3:15])[O:11]2)=[CH:13][CH:14]=1
Reactant: CC(O)(CO)COc1ccc(Br)cc1
Reactant: CC(C)=O
Product: CC1(COc2ccc(Br)cc2)COC(C)(C)O1
Temperature: 25 °C
Reaction time: 14 h
Yield: 61 %

Procedure:
3-(4-Bromophenoxy)-2-methylpropane-1,2-diol (261 mg, 1.00 mmol), acetone (10 mL), and a boron trifluoride diethyl ether complex (3 drops) were mixed. The mixture was then stirred at room temperature for 14 hours. A residue was obtained by concentrating the mixture under reduced pressure, and ethyl acetate and water were added thereto, followed by extraction. The organic layer was washed with a saline solution twice. A residue was obtained by concentrating the organic layer under reduced pressure, and the resulting residue was then subjected to chromatography refining (methylene chloride) using silica gel, obtaining 183 mg of the objective compound (yield: 61%).
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[I:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1>C1COCC1>[I:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](=[O:12])[CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=1
Reactant: CC(C)[Mg]Cl
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: C1CCOC1
Product: CC(C)C(=O)c1ccc(I)cc1
Reaction time: 0.17 h

Procedure:
A 2.0 M solution of Isopropylmagnesium chloride (10 ml, 20 mmol) was added dropwise (30 min), under nitrogen, to a stirred solution of freshly distilled 4-iodobenzoyl chloride (5.32 g, 20 mmol) and Fe(acac)3 (0.35 g, 1 mmol) in 150 ml of dry THF at room temperature. After addition, the stirring was continued for 10 min at the same temperature. The reaction was quenched by pouring the mixture into dilute hydrochloric acid and extracted with several portions of ether. The combined ether extracts were washed with aq. NaHCO3, water, and dried over Na2SO4. Removal of the organic solvents under vacuum gave the product as colorless oil. And the crude product was used for the next step without further purification.
Reaction SMILES: [C:1]([CH:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:29]=[CH:30][CH:31]=1)[C:10]([C:12]1[CH:13]=[C:14]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:15]2[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]2)=[O:11])[CH3:5])(O)=[O:2].[CH2:32]([NH2:39])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:32]([NH:39][C:1]([CH:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:29]=[CH:30][CH:31]=1)[C:10]([C:12]1[CH:13]=[C:14]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:15]2[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]2)=[O:11])[CH3:5])=[O:2])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCOC(=O)CCCc1cc(C(=O)c2cccc(NC(C)C(=O)O)c2)c2ccccn12
Reactant: CCCCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCCCCCNC(=O)C(C)Nc1cccc(C(=O)c2cc(CCCC(=O)OCC)n3ccccc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of ethyl 4- [1- [3- [(1-carboxyethyl)amino]benzoyl]indolizin-3-yl]butyrate (60 mg), heptylamine (16 mg) and 1-hydroxybenzotriazole (20 mg) in dichloromethane (3 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30 mg). The mixture was stirred for 3 hours at room temperature, evaporated and dissolved in ethyl acetate (10 ml). The solution was washed with diluted hydrochloric acid and water and dried over magnesium sulfate. The solvent was removed under reduced pressure to give ethyl 4-[1-[3-[[1(heptylcarbamoyl)ethyl]amino]benzoyl]indolizin-3-yl]butyrate (70 mg) as a yellow oil.
Reaction SMILES: N1C=CC=CC=1.[ClH:7].[NH:8]1[CH2:12][CH2:11][N:10]=[C:9]1[NH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18].Cl.[C:24]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([CH2:37][C:38](=[O:40])[NH2:39])=[C:32](O)[CH:31]=[CH:30]2)(=[NH:26])[NH2:25].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.O>[ClH:7].[ClH:7].[NH:10]1[CH2:11][CH2:12][N:8]=[C:9]1[NH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([O:19][C:32]1[CH:31]=[CH:30][C:29]2[C:34](=[CH:35][CH:36]=[C:27]([C:24](=[NH:25])[NH2:26])[CH:28]=2)[C:33]=1[CH2:37][C:38](=[O:40])[NH2:39])=[O:18]
Reactant: O=C(O)c1cccc(NC2=NCCN2)c1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: N=C(N)c1ccc2c(CC(N)=O)c(OC(=O)c3cccc(NC4=NCCN4)c3)ccc2c1
Reaction time: 2 h
Yield: 66.6 %

Procedure:
15 Milliliters of 20% hydrous pyridine was added to 634.1 mg of 3-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoic acid.hydrochloride, 676.7 mg of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 598 mg of DCC and 29.5 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 24 hours under cooling with water. Thereafter, the same procedure as in Example 1 was carried out to obtain 439.5 mg of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([F:15])([F:14])[F:13])[C:5]([F:11])=[CH:6][C:7]=1[N+:8]([O-])=O>C(O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([C:12]([F:15])([F:13])[F:14])[C:5]([F:11])=[CH:6][C:7]=1[NH2:8]
Reactant: Nc1cc(C(F)(F)F)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(F)c(C(F)(F)F)cc1N
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A mixture of 3-amino-6-fluoro-4-nitrobenzotrifluoride (328 mg, 1.45 mmol) and 10% Pd/C (50 mg) in ethanol (15 mL) was hydrogenated for 2 h at 25° C. under 25 psi H2. The catalyst was removed by filtration with celite and the solvent was removed by rota-evaporation to give 270 mg of 3,4-diamino-6-fluorobenzotrifluoride (95%) as a brown solid. 1H NMR (CDCl3): δ3.432 (br, 4H), 6.469 (d, 1H, J=8.4 Hz); 6.860 (d, 1H, J=6.6 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1ccccc1
Reactant: Brc1cncc(Br)c1
Product: Brc1cncc(OCc2ccccc2)c1
Yield: 56 %

Procedure:
3,5-Dibromopyridine was reacted with one equivalent of benzyl alcohol to give 3-benzyloxy-5-bromopyridine (56%) using the procedure described in the first paragraph of Note c. immediately above. That product was reacted with n-butyl-lithium using the procedure described in the second paragraph of Note c. except that the reaction was carried out at -110° C. The organometallic reagent so formed was reacted with tetrahydropyran-4-one using the procedure described in that Note; the product was methylated and that product was hydrogenolysed using the procedures also described in Note c. immediately above. There was thus obtained 4-(5-hydroxypyrid-3-yl)-4-methoxytetrahydropyran in 47% yield from 3-benzyloxy-5-bromopyridine.
Reaction SMILES: [C@H:1]1([O:12][C@H:13]2[C@H:22]([OH:23])[C@@H:21]([CH2:24][O:25][C@H:26]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@@H:27]3[OH:28])[O:20][C@H:15]([O:16][CH2:17][CH2:18][NH2:19])[C@H:14]2[OH:37])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3].[CH2:38]([O:45][C:46](=[O:64])[C@@H:47]([NH:53][C:54]([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55])[CH2:48][CH2:49][C:50](O)=[O:51])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:57]([O:56][C:54]([NH:53][C@@H:47]([CH2:48][CH2:49][C:50]([NH:19][CH2:18][CH2:17][O:16][C@H:15]1[O:20][C@H:21]([CH2:24][O:25][C@H:26]2[O:34][C@H:33]([CH2:35][OH:36])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@@H:27]2[OH:28])[C@@H:22]([OH:23])[C@H:13]([O:12][C@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]2[OH:3])[C@@H:14]1[OH:37])=[O:51])[C:46]([O:45][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:64])=[O:55])[C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-aminoethyl α-D-mannopyranosyl-(1→3)-[α-D-mannopyranosyl-(1→6)]-α-D-mannopyranoside (2.6 g, 4.75 mmol), and (S)-5-(benzyloxy)-4-{[(benzyloxy)carbonyl]amino}-5-oxopentanoic acid (2.0 g, 5.39 mmol) in DMF (36 mL) at 0° C. was added DMAP (580 mg, 4.75 mmol) and EDC (3.64 g, 19.00 mmol). The reaction mixture was allowed to gradually warm up to rt. After stirring for 16 hr, the reaction mixture was concentrated and the residue was purified by flash chromatography on C18 reverse phase silica gel (275 g), eluting with 10-55% AcCN in H2O to give the title compound. UPLC Method B: calculated for C40H56N2O21 900.34, observed m/e: 901.26 [M+1]; Rt=2.46 min.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([N:15]1[CH2:20][CH2:19][C:18]2[S:21][C:22]([C:24](OCC)=[O:25])=[CH:23][C:17]=2[CH2:16]1)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:15]1[CH2:20][CH2:19][C:18]2[S:21][C:22]([CH2:24][OH:25])=[CH:23][C:17]=2[CH2:16]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1cc2c(s1)CCN(C(=O)c1ccccc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2c(s1)CCN(Cc1ccccc1)C2

Procedure:
To stirred suspension of LAH (2.0 gms) a solution of ethyl 5-benzoyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (6.0 g, 19 mmol) in THF was added slowly at 0° C. After addition reaction mixture was stirred for 30 minutes and quenched with saturated NH4Cl. It was diluted with CHCl3 and filtered. The fitrate was washed with saturated brine solution and dried over anhydrous MgSO4. It was filtered and taken to next step with out purifications. Yield: 4.5 g 91%. Yellow liquid.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]([CH:17]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]([OH:25])=O)[CH2:18]3)=[O:16])[CH:12]=2)[NH:7][N:6]=1)=[O:4].[C:26]1([C:32]#[C:33][CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]([CH:17]3[CH2:21][CH2:20][N:19]([CH2:22][C:23](=[O:25])[N:37]4[CH2:38][CH2:39][CH:34]([C:33]#[C:32][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:35][CH2:36]4)[CH2:18]3)=[O:16])[CH:12]=2)[NH:7][N:6]=1)=[O:4]
Reactant: C(#CC1CCNCC1)c1ccccc1
Reactant: CNC(=O)c1n[nH]c2ccc(NC(=O)C3CCN(CC(=O)O)C3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1n[nH]c2ccc(NC(=O)C3CCN(CC(=O)N4CCC(C#Cc5ccccc5)CC4)C3)cc12
Yield: 24 %

Procedure:
A solution of [3-(3-methylcarbamoyl-1H-indazol-5-ylcarbamoyl)-pyrrolidin-1-yl]-acetic acid (0.13 mmols), 4-phenylethynyl-piperidine (0.13 mmols), 1-hydroxybenztriazole (18 mg, 0.13 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (27 mg, 0.14 mmol) and DIEA (45 μl, 0.26 mmols) was stirred overnight and directly subjected to purification by reversed phase HPLC to obtain 16 mg of the title product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[N:23]1[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:29][C:26]3[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: OCc1ccncc1
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2Cc1ccncc1

Procedure:
Compound IIo was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and pyridin-4-ylmethanol following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:13][C:12]2[C:11]([NH2:14])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]=1)[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][C:17]=1[C:25]([F:28])([F:27])[F:26].O>O1CCCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:14][C:11]2[C:12]3[CH2:13][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH2:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)=[O:24])=[CH:18][C:17]=1[C:25]([F:26])([F:27])[F:28]
Reactant: CCOC1=CCc2cccc(N)c2C1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: O
Product: CCOC1=CCc2cccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
To a stirred solution of 7-ethoxy-5,8-dihydronaphthalen-1-ylamine (0.16 g, 0.84mmol) in tetrahydrofuran (15 mL) was added 4-chloro-3-trifluoromethyl-phenylisocyanate (0.22 g, 1.0 mmol). The mixture was stirred at room temperature for 1.5 hours and was poured into water. The product was extracted with ethylacetate, and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford N-(4-chloro-3-trifluoromethyl-phenyl)-N′-(7-ethoxy-5,8-dihydro-naphthalen-1-yl)urea (0.31 g, 89% yield). Next, to a solution of N-(4-chloro-3-trifluoromethyl-phenyl)-N′-(7-ethoxy-5,8-dihydro-naphthalen 1-yl)-urea (0.21 g, 0.51 mmol) in tetrahydrofuran (20 mL) was added a solution of aqueous 1N hydrochloric acid (5 mL), and the mixture was stirred at 40° C. for 45 minutes. The mixture was neutralized with addition of 10% aqueous sodium bicarbonate solution, and extracted with ethylacetate. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford N(4-chloro-3-tri-fluoromethyl-phenyl)-N′-(7-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)urea (0.16 g, 85% yield). Next, to N-(4-chloro-3-trifluoromethyl-phenyl)-N′-7-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)urea (0.07 g, 0.18 mmol) in methanol (10 mL) was added sodium borohydride (0.04 g, 0.09 mmol) at 0° C., and the mixture was stirred for 30 minutes. The mixture was poured into water, and the product was extracted with ethylacetate. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure, and the obtained product was recrystalized from a mixture of ethylacetate/hexane (1/2) solution to give N-[4chloro-3-(trifluoromethyl)phenyl]-N′-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)urea (41 mg, 59% yield)
Reaction SMILES: [CH3:1][C@@H:2]([CH2:9][CH3:10])[CH2:3][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.[Li]CCCC.[CH3:16][Sn:17](Cl)([CH3:19])[CH3:18]>C1COCC1>[CH3:1][C@@H:2]([CH2:9][CH3:10])[CH2:3][C:4]1[S:5][C:6]([Sn:17]([CH3:19])([CH3:18])[CH3:16])=[CH:7][CH:8]=1
Reactant: C[Sn](C)(C)Cl
Reactant: CC[C@H](C)Cc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[C@H](C)Cc1ccc([Sn](C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of (S)-2-(2-methylbutyl)thiophene (4.27 g, 27.7 mmol) in dry THF (100 mL) was cooled to −78° C., and a solution of n-BuLi (2.5 M, 16.6 mL, 41.5 mmol) was then added slowly. This mixture was stirred at −78° C. for additional 10 minutes, and then allowed to warm to room temperature and stirred at room temperature for 30 minutes, before it was cooled back to −78° C. A solution of trimethylstannyl chloride (1.0 M, 43 mL, 43.0 mmol) was added slowly. This mixture was stirred at −78° C. for 2 hours, and then allowed to warm to room temperature, and stirred at room temperature overnight. The reaction was quenched by water (20 mL), and the reaction mixture was diluted with hexane, washed with water, dried over Na2SO4, and concentrated on a rotary evaporator, leading to a slightly yellow oil (8.7 g, 99.1%), which was used directly in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[Li]CCCC.CCCCCC.[CH2:23]([N:25]([CH2:44][CH3:45])[CH2:26][CH2:27][N:28]1[C:38]2[C:33](=[C:34]([C:40]([F:43])([F:42])[F:41])[CH:35]=[C:36]([I:39])[CH:37]=2)[C:31](=[O:32])[C:29]1=[O:30])[CH3:24]>C1COCC1>[CH2:44]([N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][N:28]1[C:38]2[C:33](=[C:34]([C:40]([F:42])([F:43])[F:41])[CH:35]=[C:36]([I:39])[CH:37]=2)[C:31]([OH:32])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]([F:11])([F:10])[F:9])[C:29]1=[O:30])[CH3:45]
Reactant: FC(F)(F)c1ccccc1Br
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c1cc(I)cc2C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2C(F)(F)F)c2c1cc(I)cc2C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.5 %

Procedure:
To a solution of 2-bromobenzotrifluoride (0.3 mL, 2.23 mmol) in THF (1.5 mL) was added dropwise 1.53 N BuLi in hexane (1.45 mL, 2.22 mmol) over 10 min at −78° C. and the mixture was stirred for 10 min. The resulting solution (1.2 mL, 0.82 mmol) was then added dropwise to the cooled solution of 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodoisatin (352 mg, 0.8 mmol) in THF (4 mL) at −78° C. via a syringe. The mixture was allowed to warm to room temperature and stirred for 30 min. The reaction was quenched with aqueous NaHCO3. The mixture was extracted with ethyl acetate, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography with 50:1 to 40:1 chloroform/methanol to give the title compound (96.3 mg, 21%).