Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[C:15]([CH3:21])[CH:16]=[C:17]([CH3:20])[N:18]=2)[C:13](C#N)=[CH:12]1.[OH-].[NH4+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[C:15]([CH3:21])[CH:16]=[C:17]([CH3:20])[N:18]=2)[CH:13]=[CH:12]1
Reactant: Cc1cc(C)c2c(C#N)cn(-c3ccc(C(C)C)cc3Br)c2n1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc(C)c2ccn(-c3ccc(C(C)C)cc3Br)c2n1
Yield: 65.7 %

Procedure:
A mixture of 4.00 g of 1-(2-bromo-4-isopropylphenyl)-3-cyano-4,6-dimethyl-7-azaindole and 40 mL of 65% sulfuric acid was refluxed for one hour. The solution was cooled and poured onto ice. Conc. ammonium hydroxide was added until the mixture was alkaline to pH paper. The mixture was extracted with ethyl acetate. The solution was dissolved in 60:40 hexane-ethyl acetate and passed through a short column of silica gel. The eluate was evaporated, and the residue was crystallized from 20 mL of hexane to give 2.45 g (66% yield) of 1-(2-bromo-4-isopropylphenyl)-4,6-dimethyl-7-azaindole. Mass spec: (m+H)+=343.0818; calculated, 343.0810. Rf=0.57 on silica gel with 70:30 hexane-ethyl acetate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[CH3:17])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[Br:20]Br.O>ClCCl>[CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][C:14]([Br:20])=[C:11]([CH:10]=1)[CH:12]=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: Cc1ccc(C=O)cc1OCc1ccccc1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(Br)c(C=O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a solution of 3-benzyloxy-4-methylbenzaldehyde (0.39 g) in a mixed solvent of dichloromethane (1 mL) and methanol (1 mL) was added a solution of bromine (0.410 g) in dichloromethane (0.2 mL) at 0° C. and this mixture was stirred at room temperature for 2 hours. This mixture was poured into water and the resulting mixture was extracted with dichloromethane. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.39 g).
Reaction SMILES: [CH:1]1([O:6]/[N:7]=[C:8](\[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)/[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[NH2:31][C:32]1[S:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1>C(Cl)Cl>[S:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[NH:31][C:9](=[O:11])/[C:8](=[N:7]/[O:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Nc1nc2ccccc2s1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)Nc2nc3ccccc3s2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 63.9 %

Procedure:
(E)-Cyclopentyloxyimino-(4-methanesulfonyl-phenyl)-acetic acid (37 mg, 0.12 mmol), N,N-diisopropylethylamine (92 μL, 0.53 mmol) and 2-aminobenzothiazole (27 mg, 0.18 mmol) were combined in methylene chloride (2 mL) and cooled to 0° C. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (67 mg, 0.18 mmol) was added and the cooling bath was removed. After stirring 16 h, the reaction mixture was diluted with chloroform (2 mL) and washed with saturated aqueous sodium bicarbonate solution (1.5 mL). The aqueous phase was extracted with chloroform (1.5 mL) and the combined organic phases were filtered through sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) to afford (E)-N-benzothiazol-2-yl-2-cyclopentyloxyimino-2-(4-methanesulfonyl-phenyl)-acetamide (34 mg, 43%) as a white solid: LC-MS (ESI) m/e calcd for C21H21N3O4S2 [M+] 443.10, found 444 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.66 (m, 4 H, 2×CH2), 1.90 (m, 4 H, 2×CH2), 3.11 (s, 3 H, SO2CH3), 4.95 (m, 1 H, OCH), 7.35 (brt, 1 H, Ar), 7.48 (brt, 1 H, Ar), 7.72 (d, J=8.4 Hz, 2 H, Ar), 7.83 (m, 2H, Ar), 8.03 (d, J=8.4 Hz, 2 H, Ar), 10.24 (s, 1 H, NH).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[OH:13][CH2:14][CH:15]1[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16]1.N1C=CC=CC=1>O>[CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:13][CH2:14][CH:15]2[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16]2)=[O:8])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: CC1(C)OCC(CO)O1
Solvent: O
Solvent: c1ccncc1
Product: CN(C)c1ccc(C(=O)OCC2COC(C)(C)O2)cc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
4-Dimethylaminobenzoyl chloride (1.00 g, 5 mmol) is added in one portion to a mixture of 4-hydroxymethyl-2,2-dimethyl-1,3-dioxolane (1.19 g, 10 mmol) and abs. pyridine (20 ml), and the mixture is stirred at room temperature for 10 min. The mixture is subsequently stirred at 80-90° C. for 2 h. Water (50 ml) is added, the reaction mixture is extracted with dichloromethane (3×25 ml), and the combined organic extracts are dried over magnesium sulfate. The solvent is removed in vacuo, and the residue is purified by column chromatography.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1.[N-:14]=[N+:15]=[N-:16].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[OH-].[Na+]>C(#N)C>[CH3:1][N:2]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=2)=[N:16][N:15]=[N:14]1
Reactant: [N-]=[N+]=[N-]
Reactant: CNC(=O)c1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cn1nnnc1-c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 17.7 %

Procedure:
N-Methyl-3-nitro-benzamide (30.0 g, 167 mmol) was dissolved in acetonitrile (835 mL), sodium azide (10.9 g, 167 mmol) was added and the mixture was cooled in an ice bath. Trifluoromethanesulfonic anhydride (29 mL, 172 mmol) was added dropwise at a rate which maintained the internal temperature below 3° C. The reaction mixture was stirred for 3.5 hours at 0° C. and then was poured into IN aqueous sodium hydroxide (100 mL). The organic layer was separated, dried over sodium sulfate and concentrated under vacuum to 50 mL. The solution was diluted with dichloromethane and water was added to precipitate a yellow solid (18.46 g, 54%). A second crop of crystals was obtained by concentrated the filtrate in vacuo and adding it to boiling ethyl acetate. Upon cooling to 0° C., additional material (6.07 g, 18%) was isolated by filtration. 1H NMR (300 MHz, CDCl3), δ8.67 (m, 1H), 8.49 (dd, J=8, 2 Hz, 1H), 8.31 (d, J=8 Hz, 1H), 7.94 (dd, J=8, 8 Hz, 1H), 4.22 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[C:6](=[CH:7][N:8]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:9]=2)[CH:5]=1)([O-])=O.[Cl-].[NH4+]>[Fe].C(O)C.O>[N:15]1([CH2:14][CH2:13][N:8]2[CH:7]=[C:6]3[C:10]([CH:11]=[CH:12][C:4]([NH2:1])=[CH:5]3)=[N:9]2)[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: O=[N+]([O-])c1ccc2nn(CCN3CCCC3)cc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2nn(CCN3CCCC3)cc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 5-Nitro-2-(2-pyrrolidin-1-yl-ethyl)-2H-indazole (0.250 g, 0.961 mmol), iron powder (0.536 g, 9.60 mmol) and ammonium chloride (0.0257 g, 0.480 mmol) in a 4:1 ethanol/H2O solution was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed under vacuo and the residue stirred in triethylamine/ethyl acetate (1/4, 30 mL) for 15 minutes and then filtered through a plug of silica gel. After rinsing with triethylamine/ethyl acetate (1/4), the filtrate was concentrated unde vacuo to provide the title product. 1H NMR (300 MHz, DMSO-d6) ppm 1.79 (s, 4H), 2.48 (m, 4H), 2.88 (s, 2H), 3.26 (m, 2H), 4.58 (m, 2H), 6.57 (m, 1H), 6.76 (m, 1H), 7.34 (m, 1H), 7.96 (s, 1H); MS (DCI/NH3) m/z 231 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1.[SH:21][C:22]1[N:26]([CH3:27])[CH:25]=[N:24][N:23]=1>>[CH3:20][C:17]1[N:18]=[CH:19][C:14]([NH:13][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([S:21][C:22]4[N:26]([CH3:27])[CH:25]=[N:24][N:23]=4)[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[N:15][CH:16]=1
Reactant: Cc1cnc(N)cn1
Reactant: Cn1cnnc1S
Reactant: Clc1ncnc2ccc(I)cc12
Product: Cc1cnc(Nc2ncnc3ccc(Sc4nncn4C)cc23)cn1

Procedure:
The compound of Example 19 was manufactured by the same method as in Example 1, by a similar method thereto or by a combination of such a method with a conventional method using 4-chloro-6-iodo-quinazoline, 2-amino-5-methylpyrazine and 3-mercapto-4-methyl-1,2,4-triazole.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[H][H]>[Pd].CO>[NH2:12][C:11]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: [H][H]
Reactant: COC(=O)c1cnc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cnc(N)c(N)c1

Procedure:
Methyl 6-amino-5-nitronicotinate (9.0 g, 46 mmol) and a small amount of Pd/C cat. were added to methanol (200 ml) and the mixture was hydrogenated at room temperature and atmospheric pressure until the uptake of hydrogen ceased. Following filtration through celite, the methanol was evaporated under reduced pressure to give the title compound, 7.0 g (92%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:19].[Cl-].[NH4+]>C(Cl)Cl>[CH2:1]([NH:8][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: NCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CNCc1ccccc1)c1ccc(F)cc1
Yield: 62.8 %

Procedure:
To a solution of benzylamine (1.29 g, 12.1 mmol) in methylene chloride was added triethylamine (7.6 g, 75.0 mmol), and then 2-bromo-1-(4-fluorophenyl)ethanone (3.27 g, 15.1 mmol) was added thereto. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was partitioned. The organic layer was dried over sodium sulfate and concentrated to give crude 2-(benzylamino)-1-(4-fluorophenyl)ethanone (1.85 g) as an oil. The oil (1.50 g) was dissolved in a mixed solvent of methanol (9 mL) and water (1 mL), and sodium borohydrogen (0.8 g) was added at room temperature. The reaction mixture was concentrated and extracted with tert-butyl methyl ether, and the organic layer was concentrated. Isopropyl acetate (4 mL) and heptane (4 mL) were added to the residue, and the mixture was refluxed. The precipitated crystals were collected by filtration and dried to give racemic 1-(4-fluorophenyl)-2-(benzylamino)ethanol (0.21 g). 1-(4-fluorophenyl)-2-(benzylamino)ethanol: 1H-NMR (CDCl3) δ: 2.70-2.73 (1H, m), 2.91-2.94 (1H, m), 3.80-3.88 (2H, m), 4.68-4.71 (1H, m), 7.00-7.52 (9H, m)
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H]2NC(=O)O[C@@H]2C[C@@H:11]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:10]1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.C[O+:42]([CH3:44])C.[CH2:45]([NH2:48])[CH2:46][CH3:47]>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C@@H:45]2[N:48]=[C:44]([NH:48][CH2:45][CH2:46][CH3:47])[O:42][C@@H:46]2[CH2:47][C@@H:11]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:10]1[O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1N[C@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](COCc3ccccc3)C[C@H]2O1
Reactant: C[O+](C)C
Reactant: CCCN
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCCNC1=N[C@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](COCc3ccccc3)C[C@H]2O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
A mixture of (3aR,4S,5S,6S,7aR)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)hexahydrobenzo[d]oxazol-2(3H)-one (400 mg, 0.85 mmol) and 4 Å MS (500 mg) in DCM (10 mL) was treated with trimethyloxonium tetrafluoroborate (650 mg, 4.39 mmol) for 16 h at room temperature, and followed by addition of propan-1-amine (3 mL) After stirred for additional 16 h at room temperature, the reaction mixture was poured into satd. aqueous NaHCO3 (50 mL), extracted with EtOAc (3×100 mL), washed with brine (30 mL), dried over anhydrous MgSO4, and concentrated under vacuum to give a residue, which was purified by a silica gel column, eluted with 3% MeOH and 1% ammonia (conc.) in EtOAc to give (3aR,4S,5S,6S,7aR)-4,5-bis(benzyloxy)-6-(benzyloxymethyl)-N-propyl-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazol-2-amine as yellow oil (300 mg, 69%). (ES, m/z) [M+H]+515.1; 1H NMR (300 MHz, CDCl3) δ 7.28-7.40 (m, 15H), 4.69-4.90 (m, 4H), 4.44-4.48 (m, 3H), 4.04-4.15 (m, 1H), 3.47-3.66 (m, 4H), 3.12-3.20 (m, 2H), 1.90-2.13 (m, 1H), 1.52-1.59 (m, 2H), 1.26-1.30 (m, 2H), 0.87-0.95 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:26]=[N:27][C:28](C(F)(F)F)=[CH:29][CH:30]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(C#C)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.BrC1C=NC=C([C:66]([F:69])([F:68])[F:67])C=1>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:26]=[N:27][CH:28]=[C:29]([C:66]([F:69])([F:68])[F:67])[CH:30]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cncc(Br)c1
Reactant: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cn1
Agent: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: FC(F)(F)c1cncc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[6-(trifluoromethyl)pyridin-3-yl]ethynyl}pyridazine (Intermediate 9) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 3-bromo-5-trifluoromethylpyridine.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5]([Cl:14])=[N:6][C:7]2[N:8]([N:11]=[CH:12][CH:13]=2)[C:9]=1Cl.[CH:15]([NH2:19])([CH2:17][CH3:18])[CH3:16]>C(N(CC)CC)C>[CH:15]([N:19]1[C:9]2[N:8]3[N:11]=[CH:12][CH:13]=[C:7]3[N:6]=[C:5]([Cl:14])[C:4]=2[CH2:3][CH2:2]1)([CH2:17][CH3:18])[CH3:16]
Reactant: ClCCc1c(Cl)nc2ccnn2c1Cl
Reactant: CCC(C)N
Solvent: CCN(CC)CC
Product: CCC(C)N1CCc2c(Cl)nc3ccnn3c21
Yield: 88.9 %

Procedure:
Synthesis was performed by the reaction of 5.26 g of 6-(2-chloroethyl)-5,7-dichloropyrazolo[1,5-a]pyrimidine with 4.00 g of sec-butylamine and 4.82 g of triethylamine in accordance with the synthetic process in Referential Example 9 to obtain 4.68 g (yield: 89.0%) of the intended product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].C1N=CN([C:28]([N:30]2C=N[CH:32]=[CH:31]2)=[O:29])C=1.CCN(C(C)C)C(C)C.Cl.[CH:45]12[CH2:54]C3C[CH:51]([CH2:53][CH:47]([CH2:48]3)[CH:46]1N)[CH2:52]2>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:10][CH2:11][N:12]([C:28](=[O:29])[NH:30][CH:31]3[CH:32]4[CH2:54][CH:45]5[CH2:46][CH:47]([CH2:53][CH:51]3[CH2:52]5)[CH2:48]4)[CH2:13][CH2:14]1)[CH2:8][CH:7]2[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(C)C1CC2(CCNCC2)c2c(Br)cccc21
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(C)C1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Reaction time: 1 h
Yield: 40.6 %

Procedure:
To a solution of (±)-ethyl 2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)propanoate (160 mg, 0.906 mmol) in dry CH2Cl2 was added CDI (176 mg, 1.08 mmol) and DIEA (1.16 g, 9.06 mmol) at 0° C. under N2. The mixture was stirred for 1 h, and 2-adamantanamine hydrochloride (331 mg, 0.906) in CH2Cl2 was added. The reaction mixture was stirred at rt overnight. The solvent was removed under reduced pressure to leave a residue which was purified by preparative TLC to give (±)-ethyl 2-(7-bromo-1′-(2-adamantylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)propanoate (200 mg, 41%). 1H NMR: (400 MHz, CDCl3): δ=1.11 (s, 3H), 1.22 (s, 3H), 1.26 (m, 3H), 1.45 (m, 2H), 1.52 (m, 3H), 1.73 (m, 4H), 1.85 (m, 7H), 1.95 (s, 2H), 2.44 (m, 2H), 3.02-3.26 (m, 4H), 3.79 (m, 2H), 3.98 (m, 3H), 4.25 (m, 2H), 6.93 (m, 1H), 7.01 (m, 1H), 7.35 (m, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9]Br.[N:11]1([CH2:16][C:17]([N:19]2[CH2:23][C@H:22]([NH2:24])[CH2:21][C@H:20]2[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)=[O:26])=[O:18])[CH:15]=[N:14][CH:13]=[N:12]1>>[N:11]1([CH2:16][C:17]([N:19]2[CH2:23][C@H:22]([N:24]3[CH2:9][C:4]4[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:2]3)[CH2:21][C@H:20]2[C:25]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)=[CH:32][CH:33]=2)=[O:26])=[O:18])[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: N[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Reactant: BrCc1ccccc1CBr
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](N2Cc3ccccc3C2)CN1C(=O)Cn1cncn1
Yield: 11 %

Procedure:
Proceeding as in Example 7, but substituting 1,2-bis(bromomethyl)benzene and (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-amino-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide gave Compound 260, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(isoindolin-2-yl)pyrrolidine-2-carboxamide (47 mg, 0.088 mmol, 11%). 1H-NMR (400 MHz, DMSO-d6): 10.10 (s, 1H), 8.45 (s, 1H), 7.96 (s, 1H), 7.60 (d, J=10.0 Hz, 2H), 7.29-7.17 (m, 6H), 7.03-6.95 (m, 4H), 5.34-5.30 (m, 2H), 4.56-4.52 (m, 1H), 3.95 (s, 4H), 3.71-3.60 (m, 1H), 3.52-3.46 (m, 2H), 2.31-2.24 (m, 1H), 2.17-2.09 (m, 1H). MS (EI) for C29H27FN6O3. found 527.2 (MH+).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([F:15])([F:14])[F:13])[C:3](Cl)=[O:4].[CH2:16]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:39]([C:40]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[N:37][N:36]=2)=[CH:25][CH:24]=1)[CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)C(C)C)(C)C>>[CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([F:15])([F:14])[F:13])[C:3]([N:21]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:39]([C:40]([C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[N:37][N:36]=2)=[CH:25][CH:24]=1)=[O:4]
Reactant: CCCCCNCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)C(=O)N(C)c1ccccc1C(F)(F)F
Yield: 26 %

Procedure:
Following the procedure of Example 7, Step B, N-methyl-N-[2-(trifluoromethyl)phenyl]carbamoyl chloride (from Example 7, Step A) was reacted with 1.2 equivalents of N-pentyl-N-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]amine (from Step D) in the presence of N,N-diisopropylethylamine. Flash chromatography of the crude product on silica gel (elution with 4:1 and then 3:1 hexane-EtOAc) gave two major products. Concentration of fractions containing the pure second product afforded a 26% yield of the title compound as a stiff foam, homogeneous by TLC in 3:1 EtOAc); FAB-MS m/e 772 (M+Li)+. The 1H NMR spectrum indicated the presence of two isomeric forms.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([C:15]([F:18])([F:17])[F:16])[S:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:14][CH2:13][C:12]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:9][S:10][C:11]=1[C:15]([F:16])([F:18])[F:17])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1c(-c2ccc(Cl)cc2)nsc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1c(-c2ccc(Cl)cc2)nsc1C(F)(F)F
Temperature: 0 °C

Procedure:
Into a 50-mL round-bottom flask, was placed [3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methanol (80 mg, 0.27 mmol, 1.00 equiv), dichloromethane (2.0 mL), triethylamine (83 mg, 0.82 mmol, 3.01 equiv). This was followed by the addition of MsCl (62 mg, 0.54 mmol, 2.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 1 h at 30° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×10 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.12 g of [3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methyl methanesulfonate as a yellow solid. This crude could be used for the next step directly. Mass spectrum (ESI, m/z): Calcd. for C12H9ClF3NO3S2, 372.0 (M+H). found 372.0.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:36][O:37][CH2:38][C@H:39]([CH3:88])[O:40][C:41]1[CH:42]=[C:43]([C:58]2[NH:62][C:61]([C:63]([NH:65][CH2:66][CH2:67][S:68]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=O)=[CH:60][CH:59]=2)[CH:44]=[C:45]([O:47][C:48]2[CH:53]=[CH:52][C:51]([S:54]([CH3:57])(=[O:56])=[O:55])=[CH:50][CH:49]=2)[CH:46]=1>ClCCl>[CH3:36][O:37][CH2:38][C@H:39]([CH3:88])[O:40][C:41]1[CH:42]=[C:43]([C:58]2[NH:62][C:61]([C:63]3[S:68][CH2:67][CH2:66][N:65]=3)=[CH:60][CH:59]=2)[CH:44]=[C:45]([O:47][C:48]2[CH:53]=[CH:52][C:51]([S:54]([CH3:57])(=[O:56])=[O:55])=[CH:50][CH:49]=2)[CH:46]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)[nH]2)c1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCCS3)[nH]2)c1
Reaction time: 0.17 h
Yield: 90 %

Procedure:
Triphenylphosphine oxide (2.41 g, 8.7 mmol) was dissolved in dichloromethane (20 mL), and trifluoromethanesulfonic anhydride (0.73 mL, 4.3 mmol) was added dropwise slowly at 0° C. After stirring for 10 minutes, a dichloromethane (15 mL) solution of 5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-N-[2-(tritylthio)ethyl]-1H-pyrrole-2-carboxamide synthesized in Example (25b) was added. After reaction solution was stirred at room temperature for 30 minutes, the solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out with ethyl acetate (200 mL). The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-80%) to afford the desired product (636 mg, yield 90%) as a white solid.