Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:45])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:31][CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:16][C:17]2[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:18]=2)[CH:6]=1.[OH-].[Na+]>CO>[C:39]1([CH:32]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:31][N:15]([CH2:16][C:17]2[CH:22]=[C:21]([C:23]([CH3:24])([CH3:25])[CH3:26])[CH:20]=[C:19]([C:27]([CH3:28])([CH3:29])[CH3:30])[CH:18]=2)[CH2:14][CH2:13][CH2:12][O:11][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:45])=[O:2])[CH:10]=[CH:9][CH:8]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COC(=O)Cc1cccc(OCCCN(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2)CC(c2ccccc2)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc(CN(CCCOc2cccc(CC(=O)O)c2)CC(c2ccccc2)c2ccccc2)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A solution of (3-{3-[(2,2-Diphenyl-ethyl)-(3,5-ditert-butyl-benzyl)-amino]-propoxy}-phenyl)-acetic acid methyl ester (41). (0.56 g, 0.001 mol) in methanol (6 mL) was treated with 2N NaOH (4 mL) and the mixture stirred overnight at ambient temperature. After concentration to dryness, the residue was dissolved in EtOAc (15 mL) and water was added (5 mL), the solution acidified to pH 3 with concentrated hydrochloric acid, then extracted into EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4, and then concentrated in vacuo to provide the carboxylic acid as waxy oil, which was purified by flash chromatography (9:1 CH2Cl2/MeOH) to give the desired product as oil 0.42 g in 71% yield. 1H NMR (CD3OD) δ 7.31 (s, 1H), 7.17 (m, 7H), 7.16 (s, 1H), 7.12 (t, 2H), 7.11 (s, 3H), 6.84 (d, 1H), 6.58 (s, 1H), 6.56 (d, 1H), 4.24 (t, 1H), 3.81 (s, 2H), 3.64 (t, 2H), 3.51 (s, 2H), 3.26 (d, 2H), 2.78 (t, 2H), 1.86 (t, 2H); 13C NMR (CD3OD) δ 176.2, 160.3, 152.0, 144.4, 137.9, 130.2, 129.6, 129.2, 127.5, 125.0, 122.7, 122.6, 116.6, 114.1, 66.8, 61.0, 60.3, 52.6, 50.5, 42.8, 35.7, 32.0, 27.4. Anal. Calcd for C40H49NO3: C, 81.18; H, 8.35; N, 2.37. Found: C, 81.27; H, 8.38; N, 2.22.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:24](Cl)(=[O:26])[CH3:25]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1
Yield: 51 %

Procedure:
Following procedures essentially as described in Example 90, 4-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine and acetyl chloride give the title compound in 51% yield as an off-white solid,mp 134.8° C. 1H NMR (CDCl3) δ 2.12 (s, 3H), 2.78-3.61 (br m, 4H), 6.75 (s, 1H), 6.95-7.52 (m, 13H); MS (ES) 340 (M+H). HPLC shows 95% purity.
Reaction SMILES: [CH3:1][Mg]I.[F:4][C:5]([F:19])([F:18])[CH2:6][CH:7]([CH3:17])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=O.Cl>C(OCC)C>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([CH:7]([CH3:17])[CH2:6][C:5]([F:19])([F:18])[F:4])=[CH2:1])=[CH:11][CH:12]=1
Reactant: Cc1ccc(C(=O)C(C)CC(F)(F)F)cc1
Reactant: C[Mg]I
Agent: Cl
Solvent: CCOCC
Product: C=C(c1ccc(C)cc1)C(C)CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 1.45 ml (4.34 mmol) of a 3 M solution of methylmagnesium iodide in diethyl ether were initially charged in 10 ml of diethyl ether, and 1000 mg (4.34 mmol) of 4,4,4-trifluoro-2-methyl-1-(4-methylphenyl)butan-1-one, dissolved in 5 ml of diethyl ether, were added slowly at 0 C. The reaction mixture was then slowly warmed to room temperature and stirred overnight. The reaction solution was then slowly added to 15 ml of 1 M hydrochloric acid and diluted with diethyl ether. After removal of the organic phase, the aqueous phase was extracted three more times with diethyl ether. The combined organic phases were dried over magnesium sulfate and filtered, and the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 50:1). This gave 710 mg (3.11 mmol, 71% of theory) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH:3]1[C:9](=[CH2:12])[C:10]#N.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=[O:25])C.O>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH:3]1[C:9](=[CH2:12])[CH:10]=[O:25]
Reactant: CC(=O)O
Reactant: C=C(C#N)C1CC(C)(C)CC1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C=O)C1CC(C)(C)CC1C
Temperature: 25 °C

Procedure:
2-(2,4,4-Trimethylcyclopentyl)acrylonitrile 5 is placed in toluene at 10° C. under an inert atmosphere. 1.2 eq. of Dibal (diisobutylaluminum hydride) are added thereto dropwise. The reaction medium is stirred at ambient temperature for a few hours and is then poured onto a 20:40:40 mixture of acetic acid, water and ice. The aqueous phase is extracted once with toluene. The combined organic phases are washed with a sodium bicarbonate solution and then with an aqueous sodium chloride solution. After drying over magnesium sulfate, filtering through paper and evaporating the solvent, the crude product, obtained in the form of two diastereomers in proportions of 70:30, is distilled under reduced pressure.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[C:16]([N:23]1[CH2:29][CH2:28][CH2:27][C@H:24]1[CH2:25]O)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:19]([O:18][C:16]([N:23]1[CH2:29][CH2:28][CH2:27][C@H:24]1[CH2:25][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1ccc(O)c(C(=O)OC)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c(C(=O)OC)c1
Temperature: 25 °C
Yield: 88.4 %

Procedure:
To a stirred solution of dimethyl 4-hydroxyisophthalate (1.27 g, 6.04 mmol), (S)-N-Boc-Prolinol (1.22 g, 6.06 mmol), PPh3 (1.90 g, 7.24 mmol) in THF (30 mL) was added DIAD (1.43 mL, 7.26 mmol)at room temp. The resulting stirred mixture was then heated under reflux for 15 hr. After cooling to room temp, the resulting mixture was evaporated and the residue was purified by column chromatography on silica-gel with n-hexane-EtOAc (3:1, v/v) as eluent to give 2.10 g (88%) dimethyl (S)-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinylmethoxy]isophthalate as a yellow oil. 1H-NMR (CDCl3) δ 1.26 (s, 9 H), 1.85–2.16 (m, 3 H), 3.36–3.46 (m, 2 H), 3.90 (s, 6 H), 4.11–4.31 (m, 2 H), 4.95–5.02 (m, 2 H), 7.09 (dd, H, J=9.3, 24.9 Hz), 8.11–8.14 (m, 1 H), 8.46 (d, 1 H, J=9.3 Hz)
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1.[CH3:26][NH2:27]>C(O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:8]2[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]3[N:6]=[C:2]([NH:27][CH3:26])[S:3][C:4]=3[CH:11]=[CH:10][C:9]=2[CH:12]=1
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O
Reactant: CN
Solvent: CCO
Product: CNc1nc2c(s1)C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=O

Procedure:
The product from example 44 step (viii) (0.05 g) was heated with 40% aq. Methylamine (4 ml) in ethanol (1 ml) for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was collected, dried (MgSO4) and solvent evaporated under reduced pressure. The residue was triturated with ethyl acetate/iso-hexane mixtures and the title product collected by filtration as a pale yellow solid.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C([Li])CCC.[I:25]I>O1CCCC1>[I:25][C:11]1[N:10]([S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH:12]=1
Reactant: II
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cccnc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3cccnc32)cc1
Temperature: -78 °C
Yield: 100.1 %

Procedure:
A solution of 1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [54.4 g, Reference Example 9(a)] tetrahydrofuran (1200 mL) cooled to −78° C., was treated with a solution of butyllithium in hexanes (2.5M, 92 mL) over a 20 minute period. The solution was maintained at −78° C. for 30 minutes, then a solution of iodine (101 g) in tetrahydrofuran (600 mL) was added until the iodine colour persisted (ca.300 mL). The mixture was allowed to warm slowly to ambient temperature and the solvent removed under vacuo. The residue was partitioned between ethyl acetate (1000 mL) and water (500 mL) and the aqueous layer was extracted twice with ethyl acetate (500 mL). The combined organics were combined, dried over sodium sulfate and removed under reduced pressure to give a yellow solid which was triturated with diethyl ether to give the title compound (79.6 g) as a pale yellow solid, m.p. 105-107° C. MS: 399(MH+).
Reaction SMILES: CO[C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[NH:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.Cl>CC(C)=O>[F:14][C:11]1[CH:10]=[CH:9][C:8]([N:7]2[C:3](=[O:18])[C:4]([CH3:16])([CH3:17])[NH:5][C:6]2=[O:15])=[CH:13][CH:12]=1
Reactant: COC(=O)C(C)(C)NC(=O)Nc1ccc(F)cc1
Agent: Cl
Solvent: CC(C)=O
Product: CC1(C)NC(=O)N(c2ccc(F)cc2)C1=O

Procedure:
A solution of 17.2 g (67.5 mmol) of N-[(4-fluorophenyl)-carbamoyl]-2-methylalanine methyl ester in 150 ml of 6-N aqueous hydrochloric acid and 50 ml of acetone was warmed on a steam bath for 2 hours. The mixture was then concentrated. The product, which had precipitated was dried at 40°/15 Torr and then recrystallized from toluene. The recrystallized product was dried at 50° C. for 20 hours, under greatly reduced pressure, to yield 3-(4-fluorophenyl)-5,5-dimethylhydantoin, m.p. 166°-167° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[N:8][CH:9]=1)=[O:4].Br[CH2:11][C:12]1[CH:16]=[C:15]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[O:14][N:13]=1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:11][C:12]2[CH:16]=[C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[O:14][N:13]=2)[CH:7]=[N:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1cnc[nH]1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cncn1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 250 mg 3H-Imidazole-4-carboxylic acid methyl ester in 2 ml DMF 273 mg potassium carbonate and 607 mg 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001), 460 pp. WO 0107436 A2] were added and the mixture was stirred for 2 h at RT. After addition of 5 ml water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent saponification reaction without further purification. Yield: 288 mg
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[F-:23].[Cs+].CS(C)=O>CCOC(C)=O>[F:23][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)[N:3]=1
Reactant: [F-]
Reactant: CC(C)Oc1ccc(-c2cc(-n3cccn3)cc(Cl)n2)cc1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(-c2cc(-n3cccn3)cc(F)n2)cc1
Reaction time: 18 h
Yield: 64.7 %

Procedure:
To a 2 dram vial equipped with a stir bar and charged with 2-chloro-6-(4-isopropoxyphenyl)-4-(1H-pyrazol-1-yl)pyridine (41 mg, 0.13 mmol) was added CsF (199 mg, 1.31 mmol), then DMSO (0.7 mL). The vial was placed in a 140° C. heating block with vigorous stirring for 18 hours. The reaction mixture was transfered to a separatory funnel and was diluted with EtOAc (50 mL). The organic solution was washed twice with brine:water (25 mL:25 mL); dried over MgSO4; filtered; then concentrated in vacuo to afford 2-fluoro-6-(4-isopropoxyphenyl)-4-(1H-pyrazol-1-yl)pyridine as a yellow solid (25 mg, 63%). 1H-NMR (500 MHz, CDCl3) δ 8.07 (dd, J=2.6, 0.4 Hz, 1H), 8.03-7.99 (m, 2H), 7.95 (t, J=1.4 Hz, 1H), 7.81 (d, J=1.4 Hz, 1H), 7.09 (t, J=1.6 Hz, 1H), 7.01-6.97 (m, 2H), 6.57 (dd, J=2.7, 1.7 Hz, 1H), 4.65 (spt, J=6.1 Hz, 1H), 1.39 (d, J=6.1 Hz, 6H); MS: MS m/z 298.2 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)=O.[C:22]([CH2:25][C:26](=O)[CH3:27])(=[O:24])[CH3:23].C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[Cl:21][C:17]1[CH:16]=[C:15]([C:13]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([O:8][C:9]([F:12])([F:11])[F:10])[CH:4]=3)[N:1]=[C:26]([CH3:27])[C:25]=2[C:22](=[O:24])[CH3:23])[CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)c1cccc(Cl)c1
Reactant: CC(=O)CC(C)=O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(=O)c1c(C)nc2ccc(OC(F)(F)F)cc2c1-c1cccc(Cl)c1
Yield: 55 %

Procedure:
The title compound was prepared from (2-Amino-5-trifluoromethoxy-phenyl)-(3-chloro-phenyl)-methanone [example A7] and acetylacetone according to the procedure of example 1, except that the solvent was isopropanol, and heptane/ethyl acetate (1:2) was used. Yield: 55%; MS: m/z=380 (M+H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Si:10]([O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>>[Si:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:22][CH:23]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Reactant: O=Cc1ccc(Br)cc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(C=O)cc2)cc1

Procedure:
The title compound was prepared by reacting 4-bromobenzaldehyde (730 mg, 3.97 mmol) with 4-tert-butyl-dimethylsilyoxyphenylboronic acid (1.3 g, 5.16 mmol) according to Method B to yield 600 mg (48%) of white crystal: 1H NMR (DMSO-d6): δ 0.24 (6H, s), 1.01 (9H, s), 6.94 (2H, d, J=8.54 Hz), 7.53 (2H, d, J=8.56 Hz), 7.72 (2H, d, J=8.19 Hz), 7.93 (2H, d, 8.20 Hz), 10.04 (1H, s).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[C:8]([C:25]#[N:26])=[N:7]1.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][C@@H:45]1[CH2:50][OH:51])=[O:43])([CH3:40])([CH3:39])[CH3:38]>>[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][N:47]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:27]=[CH:28][C:29]([C:31]([F:33])([F:34])[F:32])=[CH:30][C:3]=3[C:2]([F:1])([F:35])[F:36])[N:7]=[C:8]4[C:25]#[N:26])[C:17](=[O:24])[N:18]=2)[CH2:46][C@@H:45]1[CH2:50][OH:51])=[O:43])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(c2)c(C#N)nn3Cc2ccc(C(F)(F)F)cc2C(F)(F)F)S1
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(c3)c(C#N)nn4Cc3ccc(C(F)(F)F)cc3C(F)(F)F)S2)C[C@@H]1CO

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-cyano-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-5-(2-ethylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-1H-indazole-3-carbonitrile and 2-(R)—Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]([CH:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)[CH3:25])[C:16]=1[CH3:32])=[O:14].C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]([CH:26]2[CH2:31][CH2:30][CH2:29][N:28]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:27]2)[CH3:25])[C:16]=1[CH3:32])=[O:14]
Reactant: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCCNC2)c2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCCN(S(C)(=O)=O)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.8 %

Procedure:
To a solution of N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(piperidin-3-yl)ethyl)-1H-indole-3-carboxamide (20 mg, 45.81 mol) in dichloromethane (3 mL) was added triethylamine (9.27 mg, 91.63 μmol) and methanesulfonyl chloride (7.87 mg, 68.72 μmol). The mixture was stirred at room temperature for 12 hours. The mixture was evaporated and purified by preparative-HPLC (Instrument: Gilson GX281 Column: Phenomenex Gemini C18 250*21.2 mm Mobile phase A: water with 0.01 mol/1NH4HCO3; Mobile phase B: MeCN Column temperature: 30° C. Gradient: 23-53% B 10 min) to afford the title compound (7 mg, yield: 29.69%). LRMS (M+H+) m/z: calc'd 515.22. found 515.2. 1H NMR (400 MHz, METHANOL-d4) δ 0.94-1.12 (m, 2 H) 1.39 (br. S., 2 H) 1.57-1.70 (m, 4 H) 2.33 (s, 3 H) 2.63 (s, 3 H) 2.83 (d, J=9.54 Hz, 2 H) 2.88 (s, 3 H) 3.48 (br. S., 1 H) 3.79-3.87 (m, 1 H) 3.95 (s, 3 H) 4.38 (br. S., 1 H) 4.54 (s, 2 H) 6.28 (s, 1 H) 7.07-7.17 (m, 2 H) 7.58 (d, J=8.03 Hz, 1 H) 7.72 (d, J=7.53 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].O=S(Cl)Cl.[CH3:14]O>>[CH3:14][O:8][C:7]([C:6]1[CH:5]=[CH:4][S:3][C:2]=1[Br:1])=[O:9]
Reactant: O=C(O)c1ccsc1Br
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccsc1Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Bromothiophene-3-carboxylic acid (5.0 g, 24 mmol, 1 eq.) was dissolved in MeOH (100 mL) and the mixture was degassed and purged with nitrogen (2×). SOCl2 (15 mL, 0.2 mol, 8.3 eq.) was added dropwise and the resulting mixture was stirred for two days at room temperature. The mixture was then concentrated and DCM (150 mL) was added. Saturated NaHCO3 (20 mL) was added, and the resulting mixture was stirred at room temperature for 15 minutes. The organic layer was washed with saturated NaHCO3 (20 mL), water (20 mL), and saturated aqueous NaCl (20 mL), then dried over Na2SO4, filtered and concentrated to yield 2-bromothiophene-3-carboxylic acid methyl ester (5.1 g) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3(O)[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(c2ccc3c(N)ncnn23)CC1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(N)ncnn23)CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxyazepane-1-carboxylate (2.45 g, 7.05 mmol) and triethylamine (2.95 mL, 21.2 mmol) in CH2Cl2 (49 mL) was added trifluoroacetic anhydride (1.99 mL, 14.1 mmol), dropwise. The ice bath was removed and the mixture was stirred at rt for 3 h. The reaction was quenched with H2O (40 mL) and the layers were separated. The organic phase was washed with brine, dried (Na2SO4), and concentrated to dryness. The crude residue was purified by ISCO® chromatography using 1:1 ethyl acetate/hexanes to afford 1.66 g (72%) of the desired product. ES-MS m/z 330.11 [M+H]+, HPLC RT (min) 2.47.
Reaction SMILES: [C:1]1([Si:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(Cl)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:16].[K+]>CC(C)=O.O>[C:1]1([Si:7]2([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:16][Si:7]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:16][Si:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:16][Si:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:16]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: c1ccc([Si]2(c3ccccc3)O[Si](c3ccccc3)(c3ccccc3)O[Si](c3ccccc3)(c3ccccc3)O[Si](c3ccccc3)(c3ccccc3)O2)cc1
Yield: 94.1 %

Procedure:
A mixture of 510 g of diphenyldichlorosilane in 500 ml of acetone was added dropwise in the course of 3 hours to a hot solution, at 60° C, of 340 g of KOH in 1 l of water, while stirring vigorously. The acetone and a little water were then distilled off and, after cooling the residue, the crystalline octaphenylcyclotetrasiloxane was filtered off and washed with water. After drying, 376 g (94% yield) of octaphenylcyclotetrasiloxane of melting point 187° C (metastable crystal modification) were obtained. After recrystallization from toluene, the product had a melting point of 201° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:24]=[N:25][N:26]([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=5)[CH:27]=4)=[CH:21][N:20]([S:36]([C:39]4[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=4)(=[O:38])=[O:37])[C:17]3=[N:18][CH:19]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:46][C@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:24]=[N:25][N:26]([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=5)[CH:27]=4)=[CH:21][N:20]([S:36]([C:39]4[CH:40]=[CH:41][C:42]([CH3:43])=[CH:44][CH:45]=4)(=[O:38])=[O:37])[C:17]3=[N:18][CH:19]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:46][C@@H:47]([OH:48])[CH3:49])[CH2:12][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)c(F)c4)cnc32)cc1
Reactant: C[C@H]1CO1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)c(F)c4)cnc32)cc1
Yield: 76.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 5-(3-fluoro-4-(piperazin-1-yl)phenyl)-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (120 mg. 0.192 mmol) was alkylated using (S)-2-methyloxirane (14 mg, 0.23 mmol), DIPEA (50 mg, 0.384 mmol) and ethanol (5 mL) to get 100 mg (76.9% yield) of the titled compound. MS: m/z=683.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.Br[CH2:18][CH2:19][CH2:20][Cl:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:21][CH2:20][CH2:19][CH2:18][O:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OB(c2ccc(OCCCCl)cc2)OC1(C)C
Temperature: 25 °C

Procedure:
To a round-bottom flask was added 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (11.0 g, 50 mmol), 1-bromo-3-chloropropane (9.88 mL, 100 mmol), potassium carbonate (20.7 g, 150 mmol), and acetonitrile (100 mL). The reaction mixture was heated to reflux for 24 h. The reaction was cooled to room temperature and was filtered. The filtrate was concentrated to give crude 2-[4-(3-chloro-propoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane. This material was used for next step without purification.