Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([N:18]=[C:19]=S)[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC1CC2C(CC=1)=CC=CC=2N=C=S)C.[N:38]([CH2:41][C:42]([C:44]1[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=1)=[O:43])=[N+]=[N-]>>[C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([NH:18][C:19]3[O:43][C:42]([C:44]4[CH:49]=[CH:48][C:47]([C:50]([F:51])([F:52])[F:53])=[CH:46][CH:45]=4)=[CH:41][N:38]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=NCC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NC1CCc2cccc(N=C=S)c2C1
Agent: CCOC1=CCc2cccc(N=C=S)c2C1
Product: CC(C)(C)OC(=O)NC1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Yield: 36.8 %

Procedure:
The title compound was prepared using the procedure as described in Example 1H, substituting the product of Example 20F (215 mg, 0.706 mmol) for the product of Example 1F, and the product of Example 1G (194 mg, 0.848 mmol). The crude product was purified by flash chromatography eluting with 20% EtOAc/hexane which gave 123 mg (37%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 9.32 (br s, 1H), 7.75 (m, 4H), 7.60 (s, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.12 (t, J=7.8 Hz, 1H), 6.98 (br d, 1H), 6.88 (d, J=7.5 Hz, 1H), 3.64 (m, 1H), 3.02 (m, 1H), 2.84 (m, 2H), 2.42 (m, 1H), 1.87 (m, 1H), 1.60 (m, 1H), 1.39 (s, 9H); MS (ESI+) m/z 474 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6][CH2:5]2.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[N:13]1([C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[CH:8]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CCCc2cc(Br)ccc21
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)CCC(N1CCCC1)=C2
Yield: 97.4 %

Procedure:
To a 250 ml round bottomed flask was added 5.00 g (22.21 mmol) of the 6-bromotetralone afforded above in Step B; 70 ml of dry toluene and 3.1 g (3.7 ml) of pyrrolidine. The flask was equipped with a Dean-Stark trap, a condenser, a nitrogen inlet tube and a magnetic stirrer and the reaction refluxed for four hours. The solvent was evaporated under vacuum to afford 6.02 g (97.4%) of the subtitle compound as a brown crystalline material which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH2:12][OH:13])[N:11]=[C:4]2[N:3]=1>ClCCCl.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH:12]=[O:13])[N:11]=[C:4]2[N:3]=1
Reactant: Cc1cc(C)n2nc(CO)nc2n1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(C)n2nc(C=O)nc2n1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
A slurry of 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-methanol (0.3 g, 1.7 mmol) from step 7 above and IBX (1.4 g, 5.0 mmol) in 1,2-dichloroethane (22 mL) was stirred at 80° C. for 18 hours. The reaction was cooled to room temperature, and diluted with 100 mL CH2Cl2. After the solids were removed by filtration, the solvent was removed by rotary evaporation to give a yellow solid. The solid was purified by flash chromatography to give the desired product (229 mg, 77% yield). 1H NMR (CDCl3) δ: 2.72 (s, 3 H), 2.86 (s, 3 H), 6.96 (s, 1 H), 10.24 (s, 1 H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:11])[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[Br:12]Br>C(O)(=O)C>[Br:12][C:5]1[S:1][C:2]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:3]=2[CH:4]=1
Reactant: O=C1CCCCc2sccc21
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C1CCCCc2sc(Br)cc21
Temperature: -5 °C
Reaction time: 1 h

Procedure:
To a solution of 5,6,7,8-tetrahydro-cyclohepta[b]thiophen-4-one (0.5 g, 3 mmol) in 50% aqueous acetic acid (5 mL), cooled to −5° C., was added dropwise a solution of bromine (0.15 mL) in acetic acid (3 mL). The reaction mixture was stirred at −5° C. for 1 hour and quenched into aqueous sodium acetate. The resulting precipitate was filtered off to give the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 7.36 (s, 1 H), 3.01 (m, 2 H), 2.71 (m, 2H), 1.94 (m, 4 H); MS (DCI/NH3) m/z 245 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH:10]3[C:16]4[CH:17]=[C:18]([OH:22])[C:19]([Cl:21])=[CH:20][C:15]=4[CH2:14][CH2:13][N:12]([CH3:23])[CH2:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[I-].[K+].[CH3:26][O:27][CH2:28]Cl>C(O)C>[O:1]1[C:5]2[C:6]([CH:10]3[C:16]4[CH:17]=[C:18]([O:22][CH2:26][O:27][CH3:28])[C:19]([Cl:21])=[CH:20][C:15]=4[CH2:14][CH2:13][N:12]([CH3:23])[CH2:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COCCl
Reactant: CN1CCc2cc(Cl)c(O)cc2C(c2cccc3ccoc23)C1
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: COCOc1cc2c(cc1Cl)CCN(C)CC2c1cccc2ccoc12
Reaction time: 3 h

Procedure:
(+)-5-(7-benzofuranyl)-8-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol (1.64 g, 0.005 mol) is suspended in dry ethanol (50 ml). Potassium-tert.-butylate (1.12 g, 0.010 mol) and potassiumiodide (0.10 g) are added. To the resulting solution chloromethyl methyl ether (0.84 g, 0.010 mol) is added. The reaction mixture is stirred for 3 hours. The resulting suspension is filtered and the filtrate evaporated to dryness under reduced pressure. The residue is chromatographed on a silicia-gel column, using dichloromethane/methanol (25:1) as the eluent. The fractions containing the product are collected and evaporated to dryness under reduced pressure.
Reaction SMILES: Br[C:2]1[C:15]2[NH:14][C:13]3[CH2:12][CH2:11][C:10]([CH3:17])([CH3:16])[CH2:9][C:8]=3[C:7](=[O:18])[C:6]=2[C:5]([C:19]([O:21][CH3:22])=[O:20])=[CH:4][CH:3]=1.C(OCC)(=O)C>[Pd].CO>[CH3:16][C:10]1([CH3:17])[CH2:9][C:8]2[C:7](=[O:18])[C:6]3[C:5]([C:19]([O:21][CH3:22])=[O:20])=[CH:4][CH:3]=[CH:2][C:15]=3[NH:14][C:13]=2[CH2:12][CH2:11]1
Reactant: COC(=O)c1ccc(Br)c2[nH]c3c(c(=O)c12)CC(C)(C)CC3
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CC(C)(C)CC3
Temperature: 25 °C
Reaction time: 6 h
Yield: 105.1 %

Procedure:
A mixture of methyl 4-bromo-7,7-dimethyl-9-oxo-5,6,7,8,9,10-hexahydro-acridine-1-carboxylate (4.0 g, 11 mmol), ethyl acetate (300 mL), Pd/C (5% Pd on carbon, 50% water, 4.0 g) was stirred at room temperature under an atmosphere of hydrogen for 6 hours. Methanol (100 mL) and Pd/C (5% Pd on carbon, 50% water, 8.0 g) was added to the mixture and stirred for another 1 hour. The mixture was filtered through celite and the filtrate was concentrated to give the desired product (3.3 g, crude) which was used to next step without further purification. 1H NMR (DMSO-d6) δ 11.70-11.72 (m, 1H), 7.60-7.63 (m, 2H), 7.13-7.14 (m, 1H), 3.79 (s, 3H), 2.76-2.77 (m, 2H), 2.23 (s, 2H), 1.55-1.57 (m, 2H), and 0.97 (s, 6H). MS (ESI) m/e [M+1]+286.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[C:49]([Cl:52])[CH:48]=[CH:47][C:46]=1[Cl:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:46]([Cl:53])=[CH:47][CH:48]=[C:49]([Cl:52])[C:50]=3[Cl:51])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccc(Cl)c(CBr)c1Cl
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3c(Cl)ccc(Cl)c3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1,3,4-trichlorobenzene and isolated as white solid. MS (m/e): 475.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[S:6][C:7]([S:10](Cl)(=[O:12])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1>>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][S:10]([C:7]2[S:6][C:5]3[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][C:4]=3[C:8]=2[CH3:9])(=[O:12])=[O:11])=[CH:19][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: Cc1ccc(N)cc1N1CCN(C)CC1
Product: Cc1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)cc1N1CCN(C)CC1

Procedure:
The title compound (E142) was prepared from 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride and 4-methyl-3-(4-methylpiperazin-1-yl)benzenamine according to the method of Example 1 MH+32 448/450.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:5]=1[CH:6]=[C:7]1[S:11]C(=S)N[C:8]1=[O:13])([OH:3])=O.Cl.[OH-:21].[Na+]>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:4]2[C:1](=[O:3])[S:11][C:7]([C:8]([OH:21])=[O:13])=[CH:6][C:5]=2[CH:14]=1
Reactant: COc1ccc(C(=O)O)c(C=C2SC(=S)NC2=O)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COc1ccc2c(=O)sc(C(=O)O)cc2c1

Procedure:
A solution of the 5-(2-carboxy-5-methoxybenzylidene)rhodanine of Example 4 in dilute sodium hydroxide (35 ml. of 20% NaOH + 11 ml. H2O) is refluxed for one hour and then poured into dilute HCl. The resulting pale yellow solid is collected and recrystallized repeatedly from ethanol to give 6-methoxy-1-oxo-1H-2-benzothiopyran-3-carboxylic acid as pale yellow crystals, m.p. 278°-279°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](C)(C)C)[S:10][C:3]=12.Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[N:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[N:17]=3)[S:10][C:3]=12
Reactant: COc1cccc(Br)n1
Reactant: C[Sn](C)(C)c1cc2nccc(Cl)c2s1
Product: COc1cccc(-c2cc3nccc(Cl)c3s2)n1
Yield: 62.5 %

Procedure:
This material was prepared by coupling 7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.478 g, 1.44 mmole) with 2-bromo-6-methoxypyridine (0.177 ml, 1.44 mmole) using tereakis(triphenylphosphine)palladium(0) (67 mg) as catalyst in a manner as previously described for example 39b to give a pale yellow solid (0.249 g, 63%). 1H NMR (300 MHz, CDCl3) δ 8.56 (1H, d, J=5.1 Hz), 7.98 (1H, s), 7.66 (3H, m), 6.75 (1H, d, J=8.3 Hz), 4.05 (3H, s); ESIMS (MH+): 276.95.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][SH:6])C.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:4][C:5]2[S:6][CH:15]=[CH:14][C:13]=2[CH:12]=1
Reactant: CCOC(CS)OCC
Reactant: Clc1ccccc1
Product: Clc1ccc2sccc2c1
Temperature: 0 °C
Yield: 90 %

Procedure:
In a 250 mL 2-neck round flask, 4-chlorophenyl) (2,2-diethoxyethyl)sulfane (5 g, 19 mmol) and chlorobenzene (4 mL) were poured, and then the reaction mixture was added to a polyacrylic acid (PAA) reaction solution (5 g) obtained after boiling in chlorobenzen (5 mL). After the reaction, ice water (25 mL) was added to the mixture, and the mixture was washed with brine (50 mL) and dried over Na2SO4. The mixture was subjected to column chromatography using petroleum ether to give 2.9 g of white solid (90% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:25][NH:26][C:27](=[O:43])[C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:31]3[CH:32]=[CH:33][C:28]([C:27]([NH:26][CH3:25])=[O:43])=[CH:29][CH:30]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCC3)nc(Cl)nc21
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CCC4)c23)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 65.7 %

Procedure:
To a degassed mixture of 2-chloro-4-cyclobutoxy-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (1.1 equiv) and tripotassium phosphate trihydrorate (3.0 equiv) in a 9:1 mixture of 1,4-dioxane and water (0.125 M) was added palladium 1,1-bis(diphenylphosphion)ferrocene dicholoride (0.1 equiv). The reaction mixture was stirred at 80° C. for 4 h. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (1% MeOH in DCM) to afford the desired product (65.7% yield) as a yellow solid. MS (ESI) m/z 487.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>>[CH3:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:5]3[C:6]([F:8])=[CH:7][C:2]([N:26]4[CH2:30][CH2:29][CH2:28][C:27]4=[O:31])=[CH:3][C:4]=3[F:25])=[O:10])[CH2:12][CH2:13]2)=[N:18][CH:19]=[C:20]([CH3:24])[CH:21]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4CCCC4=O)cc3F)CC2)c(C)c1
Yield: 70.3 %

Procedure:
Using (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (200 mg) described in Preparation Example 111 and pyrrolidin-2-one (44 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (142 mg) was obtained.
Reaction SMILES: C[O:2][CH:3]1[NH:7][C:6](=O)[CH2:5][CH2:4]1.[CH2:9]([Si](C)(C)C)[C:10]#[CH:11]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH:9]([CH:6]1[NH:7][C:3](=[O:2])[CH2:4][CH2:5]1)=[C:10]=[CH2:11]
Reactant: COC1CCC(=O)N1
Reactant: C#CC[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: C=C=CC1CCC(=O)N1
Reaction time: 0.5 h

Procedure:
A solution of 5-methoxypyrrolidin-2-one (34) (2.55 g, 33.3 mmol), propargyl trimethylsilane (3.77 g, 33.7 mmol) and CH2Cl2 (100 mL) was cooled to 0° C. To this solution was added TiCl4 (4.9 mL, 44.4 mmol) in CH2Cl2 (20 mL) over a 15 min period at ≤3° C. After stirring for 30 min, the reaction was poured through silica gel (30 g), rinsed with CH2Cl2 (100 mL), and this initial filtrate (120 mL) discarded. The silica gel was then washed with 5% MeOH/CH2Cl2 (100 mL) followed by 10% MeOH/CH2Cl2 (100 mL), and the combined filtrates were washed with water (50 mL). The aqueous layer was back extracted with CH2Cl2 (4×30 mL), and the combined organic layers dried over MgSO4 and rotary evaporated (≤30° C.) to give 5-(1,2-propadienyl)-2-pyrrolidinone (35) as a brown oil: TLC (Eluant A) Rf =0.45; 1H NMR: δ6.6 (br s, 1 H, NH); 5.17 (ddd, 3J64 ≃4J68 ≃4J68 ≃6.6 Hz, 1 H, H6); 4.88 (d, 4J68' =6.4, 1 H, H8'); 4.21 (m, 1 H, H5); 2.35 (m, 3 H, H3, H4, H4'); 1.93 (m, 1 H, H3'); Cl Mass spec: m/z 124 (MH+), 84 (MH+ --C3H4).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH:13]=2)O1.[NH2:28][C:29]1[C:34]([C:35]2[O:36][C:37]3[C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=[CH:40][C:38]=3[N:39]=2)=[CH:33][C:32](Br)=[CH:31][N:30]=1.[F-].[Cs+]>CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:28][C:29]1[C:34]([C:35]2[O:36][C:37]3[C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=[CH:40][C:38]=3[N:39]=2)=[CH:33][C:32]([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19]3)[CH:13]=2)=[CH:31][N:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: COC(=O)c1cccc2nc(-c3cc(Br)cnc3N)oc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: COC(=O)c1cccc2nc(-c3cc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc3N)oc12
Temperature: 120 °C
Yield: 69.9 %

Procedure:
A mixture of bis(triphenylphosphine)palladium chloride (17.69 mg) was added to tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (380 mg), methyl 2-(2-amino-5-bromo-3-pyridyl)-1,3-benzoxazole-7-carboxylate (390 mg) and caesium fluoride (459 mg) dissolved in degassed methanol (5 ml) under argon. The resulting slurry was heated at 120° C. in the microwave for 30 minutes. The mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 1 to 4% methanol in dichloromethane. The solvent was evaporated to dryness to afford methyl 2-[2-amino-5-[1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]-3-pyridyl]-1,3-benzoxazole-7-carboxylate (365 mg) as a pale yellow solid. NMR Spectrum: (CDCl3) 1.49 (s, 9H), 1.97 (dd, 1H), 2.02 (dd, 1H), 2.16-2.23 (m, 2H), 2.84-3.01 (m, 2H), 4.06 (s, 3H), 4.19-4.40 (m, 3H), 6.88 (bs, 2H), 7.44 (dd, 1H), 7.70 (s, 1H), 7.80 (s, 1H), 7.94 (dd, 1H), 8.01 (dd, 1H), 8.40 (d, 1H), 8.48 (d, 1H); Mass spectrum: M+H+ 519;
Reaction SMILES: [Na].[C:2]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)#[N:3].[CH3:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][N:20]=1)[C:14]([NH:16][NH2:17])=O>CO>[N:7]1[CH:8]=[CH:9][C:4]([C:2]2[NH:17][N:16]=[C:14]([C:13]3[CH:18]=[CH:19][N:20]=[C:11]([CH3:10])[CH:12]=3)[N:3]=2)=[CH:5][CH:6]=1
Reactant: Cc1cc(C(=O)NN)ccn1
Reactant: N#Cc1ccncc1
Agent: [Na]
Solvent: CO
Product: Cc1cc(-c2n[nH]c(-c3ccncc3)n2)ccn1
Temperature: 260 °C
Reaction time: 0.5 h

Procedure:
Sodium (0.4 grams) is added to 4-cyanopyridine (8.3 grams, 0.08 mole) in methanol, and the solution is allowed to stand 30 minutes at room temperature. A suspension of 2-methylisonicotinic acid hydrazide (0.07 mole) in methanol (160 ml.) is added, and the resulting solution is heated at reflux for 30 minutes. After cooling, the intermediate acylamidrazone is collected by filtration. The acyclic intermediate is then heated at 260°C. for 15 minutes, after which the reaction is cooled to room temperature. Upon recrystallization from acetonitrile-water, 5-(4-pyridyl)-3-(2-methyl-4-pyridyl)-1,2,4-triazole is obtained, m.p. 245°-248°C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>C1COCC1>[O:24]=[C:23]1[NH:22][N:21]=[C:20]([CH2:25][CH2:26][CH3:27])/[C:19]/1=[C:11]1/[NH:12][C:13]2[C:18]([C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:31]([CH:28]4[CH2:30][CH2:29]4)=[O:32])=[CH:7][CH:6]=3)=[CH:10]/1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(Cl)C1CC1
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)C3CC3)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and cyclopropanecarboxylic acid chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.70 (t, J=7.33 Hz, 3H) 0.82-0.88 (m, 4H) 1.27-1.37 (m, J=7.45, 7.45, 7.45, 7.45, 7.33 Hz, 2H) 1.83 (dq, J=6.32, 6.15 Hz, 1H) 2.23 (t, J=7.33 Hz, 2H) 6.75 (s, 1H) 7.62 (t, J=7.58 Hz, 1H) 7.68 (d, J=8.59 Hz, 2H) 7.88 (td, J=13.64, 7.83 Hz, 4H) 8.14 (d, J=8.08 Hz, 1H) 10.58 (s, 1H); ESI-MS: m/z calc'd for C25H24N4O2S 444.55. found 445.3 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9](=[O:28])[C:10]([N:16]1[CH2:18][CH:17]1[C:19]1[CH:27]=[CH:26][C:22]2[O:23][CH2:24][O:25][C:21]=2[CH:20]=1)=[CH:11][C:12]([O:14][CH3:15])=[O:13]>O1CCOCC1>[CH3:7][O:8][C:9]([C:10]1[NH:16][CH:18]=[C:17]([C:19]2[CH:27]=[CH:26][C:22]3[O:23][CH2:24][O:25][C:21]=3[CH:20]=2)[C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[O:28]
Reactant: COC(=O)C=C(C(=O)OC)N1CC1c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)c1[nH]cc(-c2ccc3c(c2)OCO3)c1C(=O)OC
Temperature: 100 °C
Yield: 92.5 %

Procedure:
Cesium carbonate (110 mg, 0.30 mmol, 4.0 equiv) was added to a stirred solution of aziridine 26 (25 mg, 82 μmol, 1.0 equiv) in 1,4-dioxane (12 mL) at 25° C. The reaction vessel was sealed under argon and heated to 100° C. via oil bath for 20 h. The reaction mixture was cooled to 25° C., gravity filtered, and concentrated by rotary evaporation to afford 27 (23 mg, 92% yield) as a dark orange film. 1H NMR (500 MHz, CDCl3) δ 10.22 (br d, 1H, J=11 Hz, NH), 7.43 (dd, 1H, J=14, 11 Hz, pyrrole H), 6.80 (d, 1H, J=1.5 Hz, ArH), 6.72 (d, 1H, J=8 Hz, ArH), 6.69 (dd, 1H, J=8, 1.5 Hz, ArH), 5.93 (s, 2H, OCH2O), 3.89 (s, 3H, OCH3), 3.73 (s, 3H, OCH3); IR (neat film) 3348 (w, br), 2944 (w), 2890 (w), 1731 (m), 1651 (s), 1608 (s), 1503 (m), 1484 (m), 1444 (m) cm−1; HRMS (ESI) m/z: Calcd for C15H14NO6 (MH+) 304.0821; observed 304.0815.
Reaction SMILES: [F:1][CH2:2][CH2:3]I.CN(C)C=O.[C:10]([O:14][C:15](=[O:44])[C@@H:16]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:17][CH2:18][CH:19]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:13])([CH3:12])[CH3:11].O>C(OCC)(=O)C>[C:10]([O:14][C:15](=[O:44])[C@@H:16]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:17][CH2:18][CH:19]([CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH2:3][CH2:2][F:1])=[CH:33][CH:34]=1)[C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(CCc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: FCCI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(CCc1ccc(OCCF)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 60.2 %

Procedure:
53 mg (0.30 mmol) 1-Fluoro-2-iodoethane were dissolved in 5 ml dimethylformamide 98 mg (0.71 mmol) potassium carbonate and 100 mg (0.20 mmol) (2S,5RS)-2-tert.-Butoxycarbonylamino-5-[2-(4-hydroxy-phenyl)-ethyl]-hexanedioic acid di-tert.-butyl ester added. The mixture was stirred at room temperature over night. For workup, water and ethyl acetate were added, the phases separated and the water extracted with ethyl acetate twice. Combined organic phases were dried (Na2SO4), filtered and evaporated. The raw product was absorbed on Isolute and chromatographed on a Biotage Isolera system (SNAP NH 110 g, A=n-hexane, B=ethyl acetate, A 2 CV, A to 47% B in 9.4 CV, 5 CV 50% B, 50 mL/min, Fr. a 22 mL). Fractions 29 to 32 were collected to give 65 mg (59%) of (2S,5RS)-2-tert.-Butoxycarbonylamino-5-{2-[4-(2-fluoro-ethoxy)-phenyl]-ethyl}-hexanedioic acid di-tert.-butyl ester as clear oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:14]N1C(=O)CCC1=O.S(=O)(=O)(O)O>BrN1C(=O)CCC1=O>[Br:14][C:3]1[CH:4]=[C:5]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: CCCS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: CCCS(=O)(=O)c1ccc(C)c(Br)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
A finely ground mixture of 1-methyl-4-(propylsulfonyl)benzene (Intermediate 36; 24.80 g; 0.13 mol) and N-bromosuccinimide (26.8 g; 0.15 mol) was treated with conc. sulfuric acid (115 ml; 2.15 mol). The reaction mixture was stirred for 16 h then treated with a further portion of N-bromosuccinimide (1.33 g; 0.01 mol). The reaction solution was stirred 1 h then carefully poured into 800 mL of crushed ice. The aqueous solution was extracted with 400 mL of AcOEt. The layers were separated and the organic phase was washed first with ca. 300 mL of brine, then twice with a 1N solution of NaOH in water and twice with brine. The organic phase was dried on MgSO4, filtered and concentrated under reduced pressure to give the title compound (29.3 g, 85%) as a brown oil which solidified upon standing.