Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([OH:24])=O)[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH:27]12[CH2:35][CH:31]([CH2:32][NH:33][CH2:34]1)[CH2:30][N:29]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:28]2>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:33]3[CH2:34][C@H:27]4[CH2:35][C@H:31]([CH2:30][N:29]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:28]4)[CH2:32]3)=[O:24])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C2)C1
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Product: C[C@@H](C(=O)N1C[C@@H]2C[C@@H](CN(C(=O)OC(C)(C)C)C2)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O

Procedure:
Using (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid and 3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid, 1,1-dimethylethyl ester* and the synthetic procedure described in Example 1, the title compound was prepared. * Reference for 3,7-Diazabicyclo[3.3.1]nonane-3-carboxylic acid, 1,1-dimethylethyl ester: Alstermark, C; Andersson, K; Bjore, A; Bjorsne, M; Lindstedt, A. E; Nilsson, G; Polla, M; Strandlund, G; Ortengren, Y. PCT Int. Appl. (2000), WO 0077000.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([CH2:44][C:45]([NH2:47])=[O:46])[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:43][CH2:42][CH:41]([CH2:44][C:45]([NH2:47])=[O:46])[CH2:40][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NC(=O)CC1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(N)=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 2-piperidin-4-yl-acetamide (ChemBridge) to give the title compound. HR-MS (ES, m/z) calculated for C36H44Cl2N5O3 [(M+H)+] 664.2816, observed 664.2818.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH:23]C(=O)OC(C)(C)C)[N:15]([C:31]3[C:32]4[CH:39]([CH2:40][CH3:41])[CH2:38][CH2:37][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N)(OC(C)(C)C)=O.[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51].C(Cl)Cl>>[F:53][C:52]([F:55])([F:54])[C:50]([OH:56])=[O:51].[F:53][C:52]([F:55])([F:54])[C:50]([OH:56])=[O:51].[F:53][C:52]([F:55])([F:54])[C:50]([OH:56])=[O:51].[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH2:23])[N:15]([C:31]3[C:32]4[CH:39]([CH2:40][CH3:41])[CH2:38][CH2:37][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CNC(=O)OC(C)(C)C)cccc43)c21
Agent: CC(C)(C)OC(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CN)cccc43)c21
Reaction time: 2 h
Yield: 99.9 %

Procedure:
tert-Butyl (1′-benzyl-1-(5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methylcarbamate (422 mg, 0.762 mmol) was dissolved in a 1:1 TFA/DCM solution (10 mL). After 2 hours at room temperature, the LCMS suggested complete deprotection of the BOC amine. The reaction was concentrated to (1′-benzyl-1-(5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methanamine tris(2,2,2-trifluoroacetate) (606 mg, 0.762 mmol, 99.9% yield) as an oil. MS (APCI+) [M+H]: 454.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[C@@H:9]([NH2:17])[C@H:8]([O:18][CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])O.[Na+].[C:29](OC(=O)C)(=[O:31])[CH3:30]>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[C@@H:9]([NH:17][C:29](=[O:31])[CH3:30])[C@H:8]([O:18][CH:19]([CH2:20][CH3:21])[CH2:22][CH3:23])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](N)[C@H](OS(C)(=O)=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 190 mg of 20 and EtOAc (1.6 mL) in a 10 mL round-bottom flask equipped with a magnetic stirrer and an inert gas supply was added was added at RT aqueous 1 M sodium hydrogen carbonate (1.6 mL). To the resulting mixture was added 62 μl of acetic anhydride and the 2-phase mixture was stirred for 1 h at RT. The mixture was diluted with 2.0 mL of EtOAc, the organic phase was separated, dried (Na2SO4), filtered and the filter cake was washed with total 3.0 mL EtOAc. The filtrate was evaporated at 40° C./200-10 mbar to afford 192 mg of 22 as off white crystals.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH2:12]([Mg]Br)[CH3:13]>O1CCCC1>[OH:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH2:12][CH3:13])[C:3]([OH:5])=[O:4]
Reactant: CC[Mg]Br
Reactant: O=C(O)C(=O)c1ccccc1
Solvent: C1CCOC1
Product: CCC(O)(C(=O)O)c1ccccc1
Reaction time: 5 h

Procedure:
A solution of 2-oxo-2-phenylacetic acid (10 g, 66.6 mmol) (Acros Organics B.V.B.A., Belgium) in tetrahydrofuran (THF, 200 mL) was treated at room temperature with ethylmagnesium bromide (2.5 M, 80 mL, 200 mmol). The reaction mixture was stirred for 5 h, partitioned between ethyl acetate and 1N—HCl. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to afford 2-hydroxy-2-phenylbutanoic acid. A solution of 2-hydroxy-2-phenylbutanoic acid (100 mg, 0.55 mmol) and diisopropylethylamine (188 uL, 1.11 mmol) in N,N-dimethylformamide (2 mL) was treated at room temperature with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 290 mg, 0.55 mmol). After 15 min, (3-fluoro-5-(trifluoromethyl)phenyl)methanamine (107 mg, 0.55 mmol) was added. The reaction mixture was stirred for 3 h, partitioned between dichloromethane and 0.5N—NaOH. The aqueous layer was removed and the organic layer was washed with 0.5N—HCl. The aqueous layer was removed by filtering through a plastic fit. The organic layer was evaporated in vacuo to give the racemic mixture of the amide which was resolved using the chiral column (CiralPak AD) to give the desired product (2-1); HRMS (M+H−H2O)=338.1167; 1H NMR (500 MHz, CDCl3) δ 7.59 (d, 1H, J=7.5 Hz), 7.51 (m, 1H), 7.42 (d, 1H, J=5.0 Hz), 7.37 (t, 1H, J=7.5 Hz), 7.32 (d, 1H, J=7.0 Hz), 7.13 (t, 1H, J=9.0 Hz), 7.01 (bs, 1H), 4.52 (dq, 2H, J=15.6, 6.4 Hz), 2.83 (s, 1H), 2.36 (m, 1H), 2.12 (m, 1H), 0.94 (t, 3H, J=7.2 Hz).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]([C:18]([F:21])([F:20])[F:19])[CH2:14][CH2:15][CH2:16][CH3:17])(=O)=O)=CC=1.[OH:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.[Na].[H-]>CN(C)C=O>[F:19][C:18]([F:20])([F:21])[CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH2:11][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=1
Reactant: CCCCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCCC(CCOc1ccc(C(=O)OCC)cc1)C(F)(F)F
Temperature: 130 °C
Yield: 41.5 %

Procedure:
0.54 g of 3-trifluoromethylheptyl p-toluenesulfonate obtained in Step 1), 0.27 g of ethyl p-hydroxybenzoate and 1 ml of dimethylformamide (DMF) were placed in a round-bottomed flask, and 0.07 g of sodium 60%-hydride was added thereto together with DMF, followed by 6 hours of stirring at 130° C. After the reaction, DMF was distilled off under a reduced pressure, and water was added, followed by extraction with diethyl ether. The ether solution was dried with sodium sulfate, followed by distilling-off of the solvent to obtain 0.62 g of a crude product. The crude product was then purified by thin layer chromatography with benzene as the developer to obtain 0.22 g of ethyl p-(3-trifluoromethylheptyloxy)benzoate (yield: 42%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:13][CH3:14])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[C:15](Cl)(=[O:19])[C:16](Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[CH2:26]([C:33]1(C)[CH:37](C)[CH:36]=[CH:35]O1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([C:33]1[O:19][C:15]([CH3:16])=[C:36]([CH3:35])[C:37]=1[C:5]([C:4]1[CH:8]=[C:9]([CH2:13][CH3:14])[C:10]([O:11][CH3:12])=[C:2]([Br:1])[CH:3]=1)=[O:7])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC1C=COC1(C)Cc1ccccc1
Reactant: CCc1cc(C(=O)O)cc(Br)c1OC
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Product: CCc1cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc(Br)c1OC
Yield: 96.2 %

Procedure:
The title compound was prepared according to the procedure in Example 1, step 4, using 3-bromo-5-ethyl-4-methoxybenzoic acid (4.95 g, 19.1 mmol), oxalyl chloride (1.8 mL, 20.7 mmol), N,N-DMF (2 drops), tin(IV) chloride (2.50 mL, 21.4 mmol) and 2-benzyl-2,3-dimethylfuran (4.30 g, 23.1 mmol) to give 7.85 g (96%) of the title compound. 1H NMR: consistent.
Reaction SMILES: C(S)C1C=CC=CC=1.C(S[CH2:22][CH2:23][C:24]([O:26][CH:27]([CH2:42][S:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]CCCCC)[CH2:28][S:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]CCCCC)=[O:25])CCCCCCCCCCC.C([O-])(=O)C=C.O>C(O)C>[C:24]([O:26][CH:27]([CH2:28][S:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:42][S:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)(=[O:25])[CH:23]=[CH2:22]
Reactant: CCCCCCCCCCCCSCCC(=O)OC(CSCCCCCCCCCCCC)CSCCCCCCCCCCCC
Agent: C=CC(=O)[O-]
Agent: SCc1ccccc1
Solvent: CCO
Solvent: O
Product: C=CC(=O)OC(CSCc1ccccc1)CSCc1ccccc1

Procedure:
1,3-bis-(benzylthio)-2-propyl acrylate was prepared by using benzyl mercaptan in place of dodecanethiol in the procedure described in Steps (1) and (2) of Example 1. A solution of 14 grams of the acrylate, 5.8 grams of benzyl mercaptan and 1 milliliter of "Triton B" in 75 milliliters of ethanol was heated under reflux for 71/4 hours. The reaction mixture was allowed to cool and was then poured into water. The oil which precipitated was separated by extraction with toluene and the toluene solution was stripped on a rotary evaporator. There remained 21.0 grams of a light colored oil which was identified as 1,3-bis-(benzylthio)-2-propyl 3-(benzylthio)propionate by means of its NMR spectrum.
Reaction SMILES: [CH3:1][C:2]1[C:11]([Br:12])=[CH:10][C:9]([CH3:13])=[C:8]2[C:3]=1[C:4](=O)[CH2:5][CH2:6][S:7]2.Cl.[CH3:16][O:17][NH2:18].C(O)C>N1C=CC=CC=1>[CH3:16][O:17][N:18]=[C:4]1[C:3]2[C:8](=[C:9]([CH3:13])[CH:10]=[C:11]([Br:12])[C:2]=2[CH3:1])[S:7][CH2:6][CH2:5]1
Reactant: Cc1cc(Br)c(C)c2c1SCCC2=O
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C1CCSc2c(C)cc(Br)c(C)c21
Yield: 94.4 %

Procedure:
3.2 Grams (12 mmol) of 5,8-dimethyl-6-bromothiochroman-4-one and 1.9 g (23 mmol) of O-methylhydroxylamine hydrochloride were refluxed in a solvent mixture of 10 ml of ethanol and 10 ml of pyridine under heat for 30 minutes. The solvent was distilled off under reduced pressure, and then 50 ml of 5% hydrochloric acid was added to form a solid. The solid was recovered by filtration, washed with water and dried to give 3.4 g of 4-methoxyimino-5,8-dimethyl-6-bromothiochroman (yield 93%).
Reaction SMILES: [CH3:1][S-:2].[Na+].CC(N(C)C)=O.[Br:10][C:11]1[C:12]([CH3:25])=[C:13]([CH3:24])[C:14]2[O:18][C:17]([CH2:20]I)([CH3:19])[CH2:16][C:15]=2[C:22]=1[CH3:23].O>C(OCC)(=O)C>[Br:10][C:11]1[C:12]([CH3:25])=[C:13]([CH3:24])[C:14]2[O:18][C:17]([CH3:19])([CH2:20][S:2][CH3:1])[CH2:16][C:15]=2[C:22]=1[CH3:23]
Reactant: C[S-]
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(CI)O2
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CSCC1(C)Cc2c(C)c(Br)c(C)c(C)c2O1
Temperature: 140 °C
Reaction time: 4 h
Yield: 60.4 %

Procedure:
Sodium thiomethoxide (213 mg, 3.03 mmol) was added to a solution of DMA (3 mL) containing 5-bromo-2-(iodomethyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran (270 mg, 0.683 mmol) synthesized in Reference Example 133, and the mixture was stirred at 140° C. for 4 hours. The reaction solution was cooled to room temperature, and water and ethyl acetate were added thereto to separate an organic layer. The organic layer was washed with saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 100:0-90:10) to give 130 mg of the title compound (yield: 68%).
Reaction SMILES: C(OC[N:9]1[CH:13]=[C:12]([CH2:14][O:15][C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:20][CH:21]=2)[N:11]=[N:10]1)(=O)C(C)(C)C.[OH-].[Na+].Cl>CO.C1COCC1.O>[N:9]1[NH:10][N:11]=[C:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[N:18][CH:17]=2)[CH:13]=1
Reactant: CC(C)(C)C(=O)OCn1cc(COc2ccc(-n3cnnn3)nc2)nn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: c1cc(-n2cnnn2)ncc1OCc1cn[nH]n1
Reaction time: 0.5 h

Procedure:
To a solution of (4-((6-(1H-tetrazol-1-yl)pyridin-3-yloxy)methyl)-1H-1,2,3-triazol-1-yl)methyl pivalate (10 g, 27.9 mmol) in MeOH (60 mL) and THF (6 mL) was added sodium hydroxide (61.5 mL of a 1M solution in water). The mixture was stirred for 30 minutes and hydrochloric acid was added (61.5 mL of a 1M solution in water). The resulting solution was extracted with ethyl acetate, separated, dried over sodium sulfate, filtered and concentrated in vacuo to afford the expected product which was used in subsequent steps without further purification. 1H NMR (DMSO-d6): δ 10.07 (1H, s), 8.43-8.41 (2H, m), 8.00 (1H, d, J=8.8 Hz), 7.88 (1H, dd, J=3.2, 8.8 Hz), 6.32 (2H, s), 5.38 (2H, s), 1.08 (9H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[C:4]([CH3:13])([CH3:12])[CH2:3]1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:15][CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[C:2]([CH3:14])([CH3:1])[CH2:3][C:4]2([CH3:13])[CH3:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(c1)C(C)(C)CC2(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CC(C)(C)c2cc(CBr)ccc21
Temperature: 0 °C
Yield: 97.3 %

Procedure:
10.0 g of 1,1,3,3,5-pentamethylindane were dissolved in 125 ml of carbontetrachloride and were added to the resulting solution, 9.92 g of N-bromosuccinimide and 35 mg of 2,2′-azobisisobutyronitrile (AIBN). The reaction mixture was heated to reflux for 5 hours. The reaction was cooled to 0° C. and the succinimide was filtered off. The resulting solution was concentrated in vacuo and the residue (14.7 g) was further dissolved in 150 ml of hexane. The precipitate was again removed by filtration and the solution was concentrated in vacuo, giving 13.8 g of 5-bromomethyl-1,1,3,3-tetramethylindane as a yellow oil.
Reaction SMILES: N#N.[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([OH:21])[CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].F[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][CH:30]=1>O.CN(C=O)C>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:21][C:29]2[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][CH:30]=2)[CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc(C=O)cc2)c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 96.4 %

Procedure:
To a single necked round bottomed flask (500 mL) fitted with N2(g) balloon, Methyl 3-benzyloxy-5-hydroxybenzoate (Intermediate 5) (24 g, 93 mmol, 1 equiv.) followed by DMF (130 mL, 5 v/w) were added. To this stirring solution, potassium carbonate (38 g, 279 mmol, 3 equiv.) was added at room temperature. The mixture was stirred at the same temperature for 10 minutes. 4-Fluorobenzaldehyde (13.84 g, 111.62 mmol, 1.2 equiv.) was added. The reaction mixture was heated at 90° C. for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction was diluted with water and extracted with ethyl acetate. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate to furnish title compound as thick yellow liquid (32.5 g). The product can be purified by column chromatography by eluting with 10% ethyl acetate:pet ether as mobile phase.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[Li][CH:10](CC)[CH3:11].C(OCC)(=O)C.[NH4+].[Cl-]>C1COCC1.CO>[CH3:10][C:11]1[NH:1][C:2]2=[CH:3][N:4]=[CH:5][CH:6]=[C:7]2[CH:8]=1
Reactant: [Li]C(C)CC
Reactant: Cc1ccncc1N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc2ccncc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.2 %

Procedure:
To a stirred solution of 3-Amino-4-picoline (7 g, 64.8 mmol) in anhydrous THF (200 mL), sec-BuLi (150 mL, 1.3M in cyclohexane, 194 mmol) was added dropwise over 20 minutes at −78° C. The solution was warmed to room temperature and stirred at 3 hours. Ethyl acetate (2.3 g, 25.9 mmol) was added dropwise into the reaction at −78° C. and the mixture was stirred at the same temperature for 2 hours. Methanol (50 mL) was added dropwise into the reaction over 10 minutes. The mixture was warmed to room temperature and stirred for 1 hour. A half-saturated NH4Cl (250 mL) was added. The mixture was extracted with EA. The combined organic layers were washed with brine, dried and concentrated to afford the crude product. The crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate=10:1) to afford 2-methyl-1H-pyrrolo[2,3-c]pyridine (2.5 g, 73.5%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:18]1[O:22][C:21](=[O:23])[CH2:20][CH2:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:30][O:31][CH2:32][CH2:33]I>CN(C=O)C.O1CCOCC1>[C:1]([NH:8][C@H:9]([C@H:18]1[O:22][C:21](=[O:23])[CH2:20][CH2:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:33][CH2:32][O:31][CH3:30])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)[C@@H]1CCC(=O)O1
Reactant: COCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CCC(=O)O2)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
3.17 g (9.86 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-hydroxyphenyl)ethyl]dihydrofuran-2-(3H)-one in 190 ml of DMF/dioxane, 1: 1, are treated, under an N2 atmosphere, with 6.4 g (19.7 mmol) of Cs2CO3 and 2.0 g (9.86 mmol) of 2-methoxyethyl iodide. Since HPLC indicates that uureacted 5(S)-[1(S)-(Boc-amino)-2-(p-hydroxyphenyl)ethyl]-dihydrofuran-2-(3H)-one is still present after 18 h at RT, a further 1.2 g of 2-methoxyethyl iodide are added in portions. As soon as HPLC indicates that the reaction is complete, the reaction mixture is poured onto 190 ml of ice-water, and the whole is extracted 3× with methylene chloride. The organic phases are washed with water and saline, dried with Na2SO4 and evaporated. Stirring up the residue with hexane in an ultrasonication bath affords the title compound: TLC Rf (D)=0.08; FAB-MS (M+H)+ =380.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:12]([S:15]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)(=[O:17])=[O:16])([CH3:14])[CH3:13]>>[CH3:14][CH:12]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH2:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:20][CH:19]=1)(=[O:16])=[O:17])[CH3:13]
Reactant: Nc1nc2c(Br)cccn2n1
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)S(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1

Procedure:
8-[4-(Propane-2-sulfonyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (500.0 mg, 2.347 mmol) and 4-isopropylsulfonylbenzeneboronic acid (650.0 mg, 2.850 mmol) in a manner analogous to Step 2c. The reaction product was isolated as an off-white solid (0.317 g, 42%). MP=175-177° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.64 (d, J=6.6 Hz, 1H), 8.39 (d, J=7.4 Hz, 2H), 7.96 (d, J=7.5 Hz, 2H), 7.85 (d, J=7.4 Hz, 1H), 7.06-7.00 (m, 1H), 6.21 (br s, 2H), 3.54-3.42 (m, 1H), 1.19 (d, J=6.5 Hz, 6H). MS=317 (MH)+. 52b) [4-(4-Methyl-piperazin-1-yl)-phenyl]-{8-[4-(propane-2-sulfonyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-amine was prepared from 8-[4-(propane-2-sulfonyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.237 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (75.0 mg, 0.294 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (48.0 mg, 0.0877 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow foam (0.051 g, 44%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.46 (d, J=6.7 Hz, 1H), 8.25 (d, J=7.8 Hz, 2H), 8.02 (d, J=7.8 Hz, 2H), 7.65 (d, J=7.3 Hz, 1H), 7.49 (d, J=7.8 HZ, 2H), 7.01-6.95 (m, 3H), 6.69 (s, 1H), 3.30-3.15 (m, 5H), 2.63-2.58 (m, 4H), 2.36 (s, 3H), 1.36 (d, J=6.7 Hz, 6H). MS=491 (MH)+.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:6]=[C:5]([O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:4]=1)[NH2:2].[CH3:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=O>C(O)(=O)C.C(O)C>[CH3:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=[N:2][NH:1][C:3]1[CH:8]=[C:7]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:6]=[C:5]([O:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[N:4]=1
Reactant: NNc1cc(N2CCOCC2)nc(OCCN2CCOCC2)n1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C(=NNc1cc(N3CCOCC3)nc(OCCN3CCOCC3)n1)C(=O)N2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-[2-(4-Hydrazino-6-(morpholin-4-yl)-pyrimidin-2-yloxy)-ethyl]-morpholine (80 mg; ¼ mmol) was added to a flask along with 5-methylisatin (53 mg; ⅓ mmol) and ethanol (4 mL). One drop of acetic acid was added, and the reaction was stirred overnight at 60° C. The mixture was then filtered and the precipitate was washed with ethanol (1 mL) and dried to give 5-methyl-3-{[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazono}-1,3-dihydro-indol-2-one.
Reaction SMILES: [N:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([S:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[F:29])[N:13]=1>>[F:29][C:23]1[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][S:20][C:14]1[N:13]=[C:12]([NH:10][S:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:9])=[O:8])[CH:17]=[C:16]([O:18][CH3:19])[N:15]=1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: NS(=O)(=O)N1CCOCC1
Product: COc1cc(NS(=O)(=O)N2CCOCC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared from morpholine-4-sulfonamide (prepared according to patent WO 2004/011443, 0.20 g) and 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of Example 35, step i) (0.25 g) according to the procedure outlined in Example 1, step iv). The crude material was purified by column chromatography using EtOAc/isohexane (2:8) as eluent. Yield: 0.26 g.