Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[C:2]=[O:3].[F:4][C:5]1[C:6]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([CH:11]=[CH:12][CH:13]=1)C(O)=O.C(Cl)(=O)C(Cl)=O.[N-]=[N+]=[N-].[Na+]>O.CC(C)=O>[F:4][C:5]1[C:6]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([N:1]=[C:2]=[O:3])[CH:11]=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)c1c(F)cccc1C(=O)O
Reactant: [N-]=C=O
Agent: O=C(Cl)C(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[Si](C)(C)c1c(F)cccc1N=C=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Preparation of the intermediate isocyanate was carried out via a Curtius rearrangement. See Capson, T. L. et al., Tetrahedron Lett., 25, 3515 (1984) and references herein. To a solution of the compound prepared in (2) (3.03 g, 14.3 mmol) in CH2C12 (20 mL) was added oxalylchloride (1.30 mL, 15.0 mmol) and the resulting mixture was stirred 3 h at room temperature. The residue obtained after evaporation of the solvent was diluted with THF (10 mL) and injected with vigorous stirring to a ice-cooled solution of NaN3 (3.70 g, 57 mmol) in H2O (20 mL) and acetone (50 mL). After 15 min at 0° C. and 1 min at room temperature, the solution was extracted with Et2O (4×50 mL) and dried (Na2SO4). The residue obtained after evaporation of solvents was refluxed in toluene for 1 h 30 to provide, upon solvent removal, 2.85 g (79%) of a slightly yellow oil: IR (neat, cm−1) 2269, 1598, 1433, 1252, 1228, 846, 788; 1H NMR (300 MHz, CDCl3) δ0.38 (d, J=1.9 Hz, 9H), 6.82 (br t, J=8.3 Hz, 1H), 6.90 (br d, J=8.2 Hz, 1H), 7.25 (ddd, J1=J28.1 Hz, J36.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ0.4, 112.6 (d, JCF=26Hz), 120.5, 122.5, 131.5, 139.2, 167.4 (d, JCF241 Hz).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14]Br)[CH2:5]1)(=[O:3])[CH3:2].[OH:16][C:17]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14][N:20]2[CH2:21][CH2:22][C:17]([OH:16])([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:28]=3)[CH2:18][CH2:19]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: OC1(c2ccc(C(F)(F)F)cc2)CCNCC1
Reactant: CC(=O)N1CC(CCBr)c2ccccc21
Product: CC(=O)N1CC(CCN2CCC(O)(c3ccc(C(F)(F)F)cc3)CC2)c2ccccc21

Procedure:
In the manner described in Example 5, reaction of 1-acetyl-3-(2-bromoethyl)indoline with 4-hydroxy-4-(α,α,α-trifluoro-p-tolyl)piperidine gives white crystals, which melt at 141°-143°C., after recrystallization from dilute acetone.
Reaction SMILES: [CH3:1][C:2](=[CH2:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:11]([CH:13]=[CH2:14])=[O:12].C1(C=CC(O)=CC=1)O>>[CH:11]([C@@H:13]1[C@H:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=[C:2]([CH3:1])[CH2:10][CH2:14]1)=[O:12]
Reactant: C=CC=O
Reactant: C=C(C)/C=C/C(=O)OCC
Agent: Oc1ccc(O)cc1
Product: CCOC(=O)[C@@H]1C=C(C)CC[C@@H]1C=O
Temperature: 97.5 °C

Procedure:
A mixture of ethyl(2E)-4-methylpenta-2,4-dienoate (8.5 g, 60.6 mmol), acrolein (5.1 g, 91 mmol) and hydroquinone (67 mg, 0.6 mmol) was heated to 95-100° C. for 24 h. The mainly cis-ethyl 6-formyl-3-methylcyclohex-2-ene-1-carboxylate was isolated by distillation (60-80° C./0.5 mm Hg) and then equilibrated with freshly activated basic alumina (−2 grams of basic alumina per gram of cis-ethyl 6-formyl-3-methylcyclohex-2-ene-1-carboxylate) in benzene as solvent (−6 mL benzene per gram of cis-ethyl 6-formyl-3-methylcyclohex-2-ene-1-carboxylate). After stirring at room temperature for 6 days, the equilibration mixture was filtered through Celite™ and the filter cake was washed with ethyl acetate. (1R/S,6R/S)-Ethyl 6-formyl-3-methylcyclohex-2-ene-1-carboxylate was then purified by distillation (65° C./15 mm Hg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.CC(N(C)C)=O.C1C(=O)N(Br)C(=O)C1.[CH3:44][C@H:45]1[O:50][C@@H:49]([CH3:51])[CH2:48][N:47]([C:52](=[S:54])[NH2:53])[CH2:46]1>O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:54][C:52]([N:47]3[CH2:48][C@H:49]([CH3:51])[O:50][C@H:45]([CH3:44])[CH2:46]3)=[N:53][C:9]=2[C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C[C@@H]1CN(C(N)=S)C[C@H](C)O1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Solvent: O
Product: C[C@@H]1CN(c2nc(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(-c3ccnc(Cl)n3)s2)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
To N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide (1.5 g, 3.40 mmol) was added DMA (10 mL) and NBS (0.61 g, 3427 mmol). After stirring at rt for 10 min, (2R,6S)-2,6-dimethyl-4-morpholinecarbothioamide (0.800 g, 4.59 mmol) was added and stirring continued for 2 h. Water was added and the solid was collected by filtration and dried over two days to afford the title compound of Step A (1.80 g, 89% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 7.49-7.63 (m, 3H), 7.45 (t, J=7.6 Hz, 1H), 7.39 (t, J=6.4 Hz, 1H), 7.31 (t, J=7.8 Hz, 1H), 6.46 (d, J=5.3 Hz, 1H), 3.88 (d, J=11.4 Hz, 1H), 3.66 (br. s., 1H), 2.94 (s, 2H), 2.78 (s, 2H), 1.14 (d, J=6.0 Hz, 6H). m/z (ES+): 597 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C@@H:13]12[C:22](=O)[O:21][C:19](=[O:20])[C@@H:14]1[CH2:15][CH2:16][CH2:17][CH2:18]2>C(O)(=O)C>[C:22]1(=[O:21])[N:1]([CH:2]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3][C:4]([OH:6])=[O:5])[C:19](=[O:20])[C@H:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C@@H:13]12
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: NC(CC(=O)O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(O)CC(c1ccccc1)N1C(=O)[C@H]2CCCC[C@H]2C1=O
Temperature: 25 °C
Yield: 58 %

Procedure:
A stirred mixture 3-amino-3-phenylpropionic acid and cis-1,2-cyclohexanedicarboxylic anhydride in 10 mL of acetic acid under nitrogen was heated to reflux for 4 h and then allowed to cool to room temperature. The resulting mixture was concentrated to an orange yellow oil. This oil was crystallized from a 1/1 mixture of ethyl acetate/hexane to afford 1.77 g (58%) of 3-(cis-hexahydrophthalimido)-3-phenylpropionic acid as white crystals: 1H NMR (DMSO-d6) δ12.45 (br s, 1H, COOH), 7.33 (m, 5H, Ph), 5.48 (dd, 1H, J=6.3, 9.6, CH), 3.41 (dd, 1H, J=16.5, 9.6 Hz), 3.14 (dd, 1H, J=16.5, 6.3 Hz), 2.50 (m, 2H), 1.8-1.1 (m, 8H); 13C NMR (DMSO-d6) δ179.3, 179.2, 171.7, 138.7, 128.4, 127.5, 126.8, 50.1, 38.7, 38.6, 35.2, 23.0, 22.9, 21.1. Anal. Calcd for C17H19NO4. Theory: C, 67.76; H, 6.36; N, 4.65. Found: C, 67.52; H, 6.20; N, 4.60.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15]C(=O)C)=[O:7])=[CH:4][CH:3]=1>C(O)C.Cl>[NH2:15][C:9]1[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=1[C:6]([C:5]1[CH:19]=[CH:20][C:2]([F:1])=[CH:3][CH:4]=1)=[O:7]
Reactant: CC(=O)Nc1ccc(C)cc1C(=O)c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(N)c(C(=O)c2ccc(F)cc2)c1
Yield: 55.8 %

Procedure:
A solution of 119 g (0.44 mole of N-[2-(4-fluorobenzoyl)-4-methylphenyl]acetamide in 500 ml of 95% ethanol and 300 ml of 6N hydrochloric acid was heated at reflux for 16 hr. The solvents were removed on a roto-evaporator and the residue obtained was partitioned between concentrated ammonium hydroxide and benzene. The organic layer was concentrated and the new residue was chromatographed on silica gel, eluting with 10% ethyl acetate in hexane. The product fractions were concentrated and the residue was crystallized from a mixture of cyclohexane and hexane to give 56.3 g (61.5%) of the titled compound as bright yellow crystals, m.p. 70.0°-71.5° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH3:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][N:26]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:24][C:25]1[N:26]=[CH:27][C:28]([S:31]([N:15]([CH3:16])[C:12]2[CH:13]=[CH:14][C:9]([CH2:8][N:6]3[CH2:5][CH2:4][N:3]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C@@H:2]([CH3:1])[CH2:7]3)=[CH:10][CH:11]=2)(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N(C)S(=O)(=O)c3ccc(Cl)nc3)cc2)CCN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
D3 (500 mg, 1.57 mmol) and 2-chloro-pyridine-5-sulfonyl chloride (330 mg, 1.57 mmol) were combined in DCM (10 mL) under Ar. Triethylamine (0.44 mL, 3.13 mmol) was added and the solution stirred overnight. The solution was diluted with DCM and washed with water. The water layer was re-extracted with DCM. The combined organic layers were washed with brine, dried and concentrated. The crude product was purified by column chromatography. Elution with 0-50% Et2O/petroleum ether yielded the product as a white foam (685 mg), δH (CDCl3, 400 MHz): 1.24 (3H, d), 1.46 (9H, s), 2.01 (1H, m), 2.16 (1H, m), 2.56 (1H, d), 2.73 (1H, d), 3.10 (1H, m), 3.22 (3H, s), 3.40-3.50 (2H, AB), 3.81 (1H, d), 4.20 (1H, br.s), 7.05 (2H, d), 7.31 (2H, d), 7.42 (1H, d), 7.74 (1H, dd), 8.54 (1H, d). MS (ES+): MH+ 495.1/497.1
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[S:21]1[CH:25]=[CH:24][C:23]([C:26](Cl)=[O:27])=[CH:22]1.C(N(CC)CC)C>C(Cl)Cl>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3](=[O:20])[CH:2]([NH:1][C:26]([C:23]2[CH:24]=[CH:25][S:21][CH:22]=2)=[O:27])[N:8]=1
Reactant: O=C(Cl)c1ccsc1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1N=C(c2ccccc2F)c2ccccc2NC1=O)c1ccsc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (75 mg, 0.229 mmol), thiophene-3-carbonyl chloride (44.9 mg, 0.306 mmol) and triethylamine (42.5 μl, 0.306 mmol) were combined in CH2Cl2 (4 ml) and stirred 10 min. at 25° C. The reaction was concentrated and chromatographed on silica gel (2% MeOH in CH2Cl2) to give the title compound as a white solid from Et2O: (m.p. 238°-239°).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][C:12]([CH2:17][CH2:18]O)([CH2:15][CH3:16])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][C:12]([CH2:17][CH2:18][Cl:24])([CH2:15][CH3:16])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: CCC1(CCO)CCN(c2nc3ccc(Cl)cc3s2)CC1
Reactant: O=S(Cl)Cl
Product: CCC1(CCCl)CCN(c2nc3ccc(Cl)cc3s2)CC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
A mixture of 2-[1-(6-chlorobenzothiazole-2-yl)-4-ethyl piperidine-4-yl]ethanol (764 mg) and thionyl chloride (4 mL) were stirred at 60° C. for 1.5 hours. To the reaction solution was added ice and extracted with ethyl acetate. The organic layer was washed with sodium hydrogencarbonate and brine and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (739 mg). Yield: 92%.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[CH:14]([C:20](=[O:37])[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([NH:31][CH3:32])[C:22]=1[S:33]([CH3:36])(=[O:35])=[O:34])[C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16])(C)(C)C>C(Cl)Cl>[CH:17]1([C:15](=[O:16])[CH2:14][C:20]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:28])[F:30])=[C:23]([NH:31][CH3:32])[C:22]=2[S:33]([CH3:36])(=[O:34])=[O:35])=[O:37])[CH2:19][CH2:18]1
Reactant: CNc1c(C(F)(F)F)ccc(C(=O)C(C(=O)OC(C)(C)C)C(=O)C2CC2)c1S(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1c(C(F)(F)F)ccc(C(=O)CC(=O)C2CC2)c1S(C)(=O)=O

Procedure:
5.0 ml of trifluoroacetic acid were heated at 55°-60° C. A solution of 5.3 g (8.0 mmol; 70% purity) of tert-butyl-3-cyclopropyl-2-(3-methylamino-2-methylsulfonyl-4-trifluoromethylbenzoyl)-3-oxopropanoate in 10 ml of CH2Cl2 was added dropwise and the mixture was then heated at reflux for 15 min. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. This gave 1.22 g of product in 95% purity.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][Mg]Br>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([OH:13])([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Solvent: CCOCC
Product: CC1(O)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 36.8 %

Procedure:
3-Oxo-pyrrolidine-1-carboxylic acid tert-butyl ester [Hofmann, J. Agric. Food Chem., 46, 3902 (1998)] (0.322 g, 1.74 mmol) was dissolved in diethyl ether (5 ml), cooled with an ice bath, and treated with methylmagnesium bromide (3M in ether, 0.64 ml, 1.91 mmol). The reaction was stirred for 1 h then more methylmagnesium bromide added, and the mixture stirred for 63 h. The reaction was quenched with aqueous ammonium chloride and extracted with diethyl ether (×3). The combined organic extracts were dried and evaporated. The residue was purified by flash chromatography, eluting with 0–50% ethyl acetate in petroleum ether, to give the title compound as a sticky off-white solid (0.129 g, 37%); NMR (CDCl3) 1.41 (3H, s), 1.46 (9H, s), 1.61 (1H, s), 1.79–1.92 (2H, m), and 3.17–3.58 (4H, m).
Reaction SMILES: [F:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[C:5]([O:15]C)=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1.[OH-].[NH4+]>>[F:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[C:5]([OH:15])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2[nH]c3ccccc3c12
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Product: Oc1ccc(F)c2[nH]c3ccccc3c12
Reaction time: 0.33 h
Yield: 114.5 %

Procedure:
A mixture of 1-fluoro-4-methoxycarbazole (438 mg, 2.04 mmol) and pyridine hydrochloride (3 g) was placed into an oil bath that was preheated to 220° C. After 20 minutes, the reaction was poured onto a mixture of ice and concentrated ammonium hydroxide. The product was extracted into ethyl acetate and the extract was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was azeotroped with toluene to give 470 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH2:30][C:29](=O)[CH2:28][CH2:27]2>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:29]2[CH2:28][CH2:27][C:26]3[C:31](=[CH:32][CH:33]=[C:24]([Cl:23])[CH:25]=3)[CH2:30]2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=C1CCc2cc(Cl)ccc2C1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Product: CCCC(NC1CCc2cc(Cl)ccc2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 6-chloro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.6, 19.6, 24.3, 26.6, 27.9, 28.0, 29.2, 30.0, 36.0, 36.5, 36.6, 36.9, 53.1, 53.3, 56.0, 59.1, 60.5, 60.8, 67.3, 104.7, 126.1, 128.5, 128.7, 130.7, 130.8, 131.2, 131.5, 131.6, 133.6, 137.3, 137.7, 138.0, 172.4; MS m/z 472.4 (M+1).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([CH:26]=[CH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:14][N:15]3[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:11][CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.CCCCCC>[C:1]1([C:7]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([CH:26]=[CH:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[N:14][N:15]3[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:11][CH:10]=2)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(C(O)c3ccccc3)cc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCCCCC
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(C(=O)c3ccccc3)cc21
Temperature: 23 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of phenyl-(3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanol (68 mg, 0.15 mmol) in dichloromethane (3 mL) at 23° C. under an atmosphere of argon was added periodinane (Dess-Martin reagent) (190 mg, 0.45 mmol). The resulting mixture was stirred at 23° C. for 1 hour. The solution was then diluted with hexane (3 mL) then filtered through Celite and concentrated under reduced pressure to a solid. The crude mixture was purified by silica gel chromatography (eluting with hexane:EtOAc 9:1) to give phenyl-(3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl]-methanone (54 mg, 79% yield). Rf sm=0.41, Rf p=0.63 (7:3 hexane:EtOAc); FTIR (thin film) 3059, 2952, 2894, 1659, 1474, 1448, 1307, 1249, 1078, 836, 649 cm−1. MS (ESI) [M+H]/z Calc'd 455, found 455.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].F[P-](F)(F)(F)(F)F.CN(C(ON1C2=NC=CC=C2N=N1)=[N+](C)C)C.[NH:36]1[C:44]2[C:39](=[C:40]([C:45]3[CH:46]=[C:47]([NH2:54])[C:48]4[CH:49]=[N:50][NH:51][C:52]=4[CH:53]=3)[CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37]1>CN(C=O)C.CCN(C(C)C)C(C)C>[CH2:1]([N:3]1[C:7]([C:8]([NH:54][C:47]2[CH:46]=[C:45]([C:40]3[CH:41]=[CH:42][CH:43]=[C:44]4[C:39]=3[CH:38]=[CH:37][NH:36]4)[CH:53]=[C:52]3[C:48]=2[CH:49]=[N:50][NH:51]3)=[O:10])=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2]
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: CCn1nc(C)cc1C(=O)O
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: CCn1nc(C)cc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 0.08 h

Procedure:
1-Ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (67.8 mg) was treated with N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (168 mg) in DMF (750 μl) and DIPEA (150 μl). Reaction mixture was shaken for five min prior to treatment with 6-(1H-indol-4-yl)-1H-indazol-4-amine (50 mg) in DMF (350 μl). Reaction mixture was left to stand at 22° C. for 16 hrs. Solvent was removed in vacuo and the product re-dissolved in chloroform (0.3 ml) prior to application on to a preconditioned (methanol then chloroform) aminopropyl SPE cartridge (1 g). Product was eluted after 2 h with ethyl acetate:methanol (1:1, 3.2 ml), and concentrated under a stream of nitrogen using blow down apparatus. Purification by mass directed preparative HPLC (Method B) gave the title compound.
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.Br[C:31]1[CH:32]=[C:33]([CH2:37][C:38]([NH:40][CH3:41])=[O:39])[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:13]=[CH:14][C:15]([C:36]2[CH:35]=[CH:34][C:33]([CH2:37][C:38]([NH:40][CH3:41])=[O:39])=[CH:32][CH:31]=2)=[CH:16][CH:17]=1
Reactant: CNC(=O)Cc1cccc(Br)c1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CNC(=O)Cc1ccc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)cc1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.20 g, Example 11)), 2-(3-bromophenyl)-N-methyl-acetamide (0.244 g, Example 24a)), 2M aqueous sodium carbonate (0.265 ml) and tetrakis(triphenylphosphine)palladium (0) (0.1 g) in toluene (5 ml) and ethanol (2 ml). The reaction was heated at 110° C. for 6 hours. After cooling, the solution was concentrated under reduced pressure the residue was dissolved in methanol (10 ml), concentrated hydrochloric acid (1 ml) was added and the solution stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure the residue was neutralised using saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil which was converted to the oxalic acid salt by treatment with a saturated ethereal solution of oxalic acid to give the title compound as a gum (0.123 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:32]([F:35])([F:34])[F:33])=[CH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18]2([CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]2)[O:17][CH2:16]3)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N+:36]([CH3:39])([O-:38])=[O:37].C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH2:39][N+:36]([O-:38])=[O:37])([C:32]([F:33])([F:35])[F:34])[CH2:10][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18]2([CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24]2)[O:17][CH2:16]3)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)C=C(c3cc(Cl)cc(Cl)c3)C(F)(F)F)ccc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)CC(C[N+](=O)[O-])(c3cc(Cl)cc(Cl)c3)C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.6 %

Procedure:
To a stirred solution of tert-butyl 5′-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoyl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (Preparation 10, 1 g, 1.89 mmol) in acetonitrile (10 mL) was added nitromethane (1.013 mL, 18.93 mmol) and DBU (0.275 mL, 1.84 mmol) at room temperature. Resulting reaction mixture was stirred at room temperature for 16 hours. After consumption of starting material; reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (2×25 mL). Combined organic layers were washed with brine (60 mL), dried over sodium sulfate and concentrated under reduced pressure to get brown semi solid (1.41 g, crude). Crude compound was purified by column chromatography using silica gel (230-400 mesh). Desired compound was eluted in 10% ethyl acetate in n-hexane to get light yellow sticky liquid (1.02 g, 91.07%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 3.97 (d, J=18.64 Hz, 1H), 4.10-4.17 (m, 3H), 4.34 (d, J=9.8 Hz, 2H), 5.16 (s, 2H), 5.45 (d, J=12.32 Hz, 1H), 5.58 (d, J=12.36 Hz, 1H), 7.18 (s, 2H), 7.40-7.41 (m, 1H), 7.61 (d, J=7.92 Hz, 1H), 7.81 (s, 1H), 7.98-8.00 (m, 1H), LC-MS (m/z): 587.1 (M−H).