Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(OO)(C)(C)C.[C:12]1([CH:18]([C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)[C@H:19]([NH:60][C:61](=[O:78])[C@H:62]([CH2:74][CH:75]([CH3:77])[CH3:76])[NH:63][C:64]([O:66][CH2:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)=[O:65])[CH:20]=[CH:21][S:22]([CH:25]=[CH:26][C@@H:27]([NH:41][C:42](=[O:59])[C@H:43]([CH2:55][CH:56]([CH3:58])[CH3:57])[NH:44][C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])[CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:24])=[O:23])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOC(C)=O>C1COCC1>[C:29]1([CH:28]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:27]([NH:41][C:42](=[O:59])[C@H:43]([CH2:55][CH:56]([CH3:57])[CH3:58])[NH:44][C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])=[CH:26][CH2:25][S:22]([CH2:21][CH:20]=[C:19]([NH:60][C:61](=[O:78])[C@H:62]([CH2:74][CH:75]([CH3:77])[CH3:76])[NH:63][C:64]([O:66][CH2:67][C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=2)=[O:65])[CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:79]2[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=2)(=[O:23])=[O:24])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C=CS(=O)(=O)C=C[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)OO
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NC(=CCS(=O)(=O)CC=C(NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 63 %

Procedure:
Butyllithium (3.63 ml, 6.17 mmol, 1.7 M in pentane) was added dropwise to a solution of tert-butylhydroperoxide (2.55 ml, 8.42 mmol, 3.3 M in toluene) in freshly distilled THF (80 ml) at −78° C. under argon. A solution of Cbz-Leu-Phe-VS-Ph (3.00 g, 5.61 mmol) in dry THF (30 ml) was added dropwise. The reaction was continued to stir at −20° C. for 45 minutes (TLC Hex/EtOAc 1:1). The reaction was quenched with saturated aqueous ammonium chloride (50 ml) and allowed to warm to room temperature. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×30 ml). The extracts were then washed with aqueous sodium sulfite (10%, 3×20 ml). The combined organic layers were dried (MgSO4) and evaporated to give Cbz-Leu-Phe-AS-Ph as a white powder, yield 63%. 1H-NMR (CDCl3) δ 0.8-0.9 (2d, 6H, 2×Leu-CH3), 1.4-1.6 (m, 2H, Leu-CH2), 3.8 (s, 2H, CH2-Phe), 3.9 (d, 2H, CH2—SO2), 4.1 (m, 1H, α-H), 4.8 (t, 1H, CH═), 4.9-5.0 (b, 1H, NH), 5.1 (m, 2H, Cbz), 7.1-7.4 (m, 10H, 2×Ph), 7.5-7.7 (m, 5H, SO2-Ph), 8.4 (b, 1H, NH). 13C NMR (400 MHz, CDCl3) δ 172.1, 156.3, 144.4, 140.8, 135.7, 134.2, 133.6, 131.2, 129.5, 129.4×2, 129.3, 128.8×2, 128.7, 128.6, 128.4, 128.3, 127.8, 127.3, 126.9, 106.3, 67.6, 56.0, 55.6, 41.7, 40.4, 22.1, 21.0, 18.4. MS (FAB+) m/z 535 (M+1, 100%). Anal. Calcd. for C30H34N2O5S: C, 67.39; H, 6.56; N, 5.43. Found: C, 67.41; H, 6.56; N, 5.43.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1OCCOCCOCCOCCOCCOC1.[K].Br[CH2:44][C:45]1[C:46]([C:53]2[C:58]([Cl:59])=[CH:57][CH:56]=[CH:55][C:54]=2[Cl:60])=[N:47][O:48][C:49]=1[CH:50]1[CH2:52][CH2:51]1>O1CCCC1.C(O)(C)(C)C>[CH:50]1([C:49]2[O:48][N:47]=[C:46]([C:53]3[C:58]([Cl:59])=[CH:57][CH:56]=[CH:55][C:54]=3[Cl:60])[C:45]=2[CH2:44][O:21][C@H:18]2[CH2:19][CH2:20][C@H:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=4)=[CH:10][CH:11]=3)[CH2:16][CH2:17]2)[CH2:52][CH2:51]1
Reactant: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Reactant: COc1ccc(COc2ccc(C3CCC(O)CC3)cc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: COc1ccc(COc2ccc([C@H]3CC[C@H](OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)cc2)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
4-[4-(4-Methoxy-benzyloxy)-phenyl]-cyclohexanol (2.24 mmol, 700.00 mg) and 18-crown-6 (2.69 mmol, 710.70 mg) in tetrahydrofuran (10 mL) is treated with tert-butyl alcohol, potassium derivative (2.69 mmol, 2.69 mL; 1M in THF). The mixture is stirred for 30 minutes and 4-bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole (3.36 mmol, 1.17 g) is added. The mixture is stirred at room temperature for 5 minutes and heated to 40° C. for 1.5 h. Silica gel is added and the reaction mixture is concentrated under reduced pressure. The crude mixture is purified by silica gel flash chromatography eluting with a gradient of 10-60% EtOAc in hexanes. A second chromatography is performed on silica gel eluting with 0.5% EtOAc in DCM to yield the title compound (960 mg, 74%). MS m/z 577.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH2:12]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a solution of 4-methyl-2-nitro-phenylamine (202 mg, 1.33 mmol) and benzaldehyde (0.68 mL, 6.65 mmol) in 5 mL dry dichloromethane at room temperature, was added sodium triacetoxyborohydride (282 mg, 1.33 mmol). Then acetic acid (76 μl, 1.33 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated and the solid was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered, and the solvent was removed in vacuo. The crude material was purified by flash chromatography to yield 300 mg (1.24 mmol, 94%) of benzyl-(4-methyl-2-nitro-phenyl)-amine.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[C:11]([CH2:28][CH2:29][CH3:30])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[H-].[Na+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CN(C)C=O>[CH2:35]([O:8][C:3]([C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17][CH2:16]2)=[C:11]([CH2:28][CH2:29][CH3:30])[CH:10]=1)([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:31])[F:32])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ncc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ncc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
tert-Butyl 4-[6-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4-propylpyridin-3-yl]piperazine-1-carboxylate (60 mg, 0.126 mmol) was dried with a vacuum pump, and dissolved in N,N-dimethylformamide (2.5 mL). Sodium hydride (7.3 mg, 0.152 mmol) and benzyl bromide (17 μL, 0.139 mmol) were added sequentially under ice-cold conditions, and the mixture was stirred at room temperature overnight. The reaction solution was added water under ice-cold conditions, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone), and the title compound (54 mg (yield 76%)) was obtained as a yellow oil.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([N+:24]([O-:26])=[O:25])[C:7]([OH:23])=[C:8]([C:10]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([N+:19]([O-:21])=[O:20])[C:13]=2[OH:22])=[O:11])[CH:9]=1.Cl>C(O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([N+:24]([O-:26])=[O:25])[C:7]([OH:23])=[C:8]([CH:10]([OH:11])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([N+:19]([O-:21])=[O:20])[C:13]=2[OH:22])[CH:9]=1
Reactant: O=C(c1cc(Cl)cc([N+](=O)[O-])c1O)c1cc(Cl)cc([N+](=O)[O-])c1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(Cl)cc(C(O)c2cc(Cl)cc([N+](=O)[O-])c2O)c1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
Sodium borohydride (3.5 g) was added portionwise to a stirred solution of bis(5-chloro-2-hydroxy-3-nitrophenyl) ketone (10 g) in ethanol (150 ml) the solution being maintained at a temperature of 0° C. On completion of the addition the temperature of the solution was allowed to rise to ambient temperature and the mixture was stirred overnight at ambient temperature. The solution was diluted with water, acidified with hydrochloric acid and the product extracted into ethyl acetate. The solvent was removed by distillation under reduced pressure to give bis-(5-chloro-2-hydroxy-3-nitrophenyl)methyl alcohol (9.0 g) which on recrystallisation from ethanol/hexane had a melting point of 180° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].Cl.[NH2:17][OH:18].C(=O)([O-])[O-].[Na+].[Na+]>O.CO>[NH2:2][C:1](=[N:17][OH:18])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C(N)=NO)CC1

Procedure:
A mixture of tert-butyl 4-cyano-1-piperidinecarboxylate (2.69 g, 12.8 mmol), hydroxylamine hydrochloride (4.45 g, 64 mmol) and sodium carbonate (6.78 g, 64 mmol) in water (40 ml) and methanol (40 ml) was heated under reflux for 5 hours. The cooled mixture was concentrated under reduced pressure and the remaining aqueous solution extracted with ethyl acetate (3×). The combined organic extracts were washed with water and brine, dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound as a white solid, 2.60 g.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Mg]Cl.C1COCC1.[Cl-].[NH4+]>C(OCC)C>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([OH:4])[CH2:2][CH3:3]
Reactant: Cc1ccccc1[Mg]Cl
Reactant: CCC(=O)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)(c1ccccc1)c1ccccc1C
Yield: 92 %

Procedure:
Propiophenone (6.7 g, 50 mmol) was added dropwise to a solution of 2-methylphenylmagnesium chloride (30 ml of a 2.0 M solution in diethyl ether) and dry THF (50 ml) under a nitrogen atmosphere. When the addition was complete the reaction mixture was heated at reflux temperature for 5 h. Excess of a saturated ammonium chloride solution was added and the mixture was extracted with diethyl ether (2×100 ml). The combined organic extracts were dried over potassium carbonate and the solvent was evaporated in vacuo to give 10.4 g (92%) of 1-(2-methyl phenyl)-1-phenyl-1- propanol. TLC: rf=0.50 (SiO2 ; n-heptane/THF=7:3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:41]2[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]2)=[O:17])=[CH:18][CH:19]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(CCNC(=O)OC(C)(C)C)cc2)CC1

Procedure:
4-(2-Tert-butoxycarbonylamino-ethyl)-benzoic acid was reacted with WSCI, HOBt, triethylamine and N-methylpiperazine in dichloromethane, to obtain a crude product of {2-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester, and then treated with TFA, to obtain [4-(2-amino-ethyl)-phenyl]-(4-methyl-piperazin-1-yl)-methanone. Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and [4-(2-amino-ethyl)-phenyl]-(4-methyl-piperazin-1-yl)-methanone (39 mg) instead of 4-(4-ethyl-piperazin-1-yl)-2,6-difluoro-phenylamine used in Step D in Example 1-D-18, in the same manner as Step D in Example 1-D-18, a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-ethyl}-amide was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-294) as a colorless powder (121 mg, 97%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]2[CH2:21][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[CH3:22][S:23]([NH:26][C:27]1[CH:42]=[CH:41][C:30]2[NH:31][C:32]([CH2:37][C:38](O)=[O:39])=[N:33][S:34](=[O:36])(=[O:35])[C:29]=2[CH:28]=1)(=[O:25])=[O:24].Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:38](=[O:39])[CH2:37][C:32]2[NH:31][C:30]3[CH:41]=[CH:42][C:27]([NH:26][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:28][C:29]=3[S:34](=[O:35])(=[O:36])[N:33]=2)[C@H:10]2[CH2:21][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (1S,2R,3S,4R)-3-(4-fluorobenzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (100.6 mg, 0.345 mmol) in N,N-dimethylformamide (3.0 mL) was added (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 120.8 mg, 0.362 mmol), 4-dimethylaminopyridine (10.6 mg, 0.086 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (70.9 mg, 0.362 mmol). After stirring at 25° C. for 12 h, the mixture was diluted with ethyl acetate and acidified with 1.0M aqueous hydrochloric acid solution to pH 1. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo, and dried under high vacuum to afford the crude product, (1S,2R,3S,4R)-3-{(4-fluorobenzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester, as a faintly yellow oil. The crude product was used in the next step without further purification. LC-MS (ESI) calcd for C27H31FN4O7S2 606.16, found 607.2 [M+H+].
Reaction SMILES: C(#N)C.[CH3:4][O:5][C:6]1[C:11]([CH2:12]Cl)=[CH:10][CH:9]=[CH:8][N:7]=1.[CH2:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1/[CH:28]=[CH:29]/[CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:4][O:5][C:6]1[C:11]([CH2:12][N:33]2[CH2:34][CH2:35][CH:30](/[CH:29]=[CH:28]/[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH2:20][CH:15]3[CH2:14][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:31][CH2:32]2)=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: C(=C/C1CCNCC1)\c1ccccc1OCC1CCCCC1
Reactant: COc1ncccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ncccc1CN1CCC(/C=C/c2ccccc2OCC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To acetonitrile (10 ml) were added 500 mg of 2-methoxy-3-(chloromethyl)pyridine, 1.04 g of 4-[(E)-2-[(2-cyclohexylmethyloxy)phenyl]-1-ethenyl]piperidine and 531 mg of potassium carbonate, followed by stirring at room temperature overnight. Ethyl acetate was added to the reaction solution, and the mixture was filtered through alumina-silica gel. Then, the solvent was evaporated, and the crude product was purified by silica gel column chromatography (hexane:ethyl acetate=8:1), to give 961 mg of the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:20]([O:12][C:11](=[O:13])[C@@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
To a solution of 11.19 g (59.1 mmol) of (R)-N-tert-butoxycarbonylalanine in 70 mL of N,N-dimethylformamide was added 6.7 g (48.5 mmol) of K2CO3, and 6.9 mL (58.0 mmol) of benzyl bromide. The reaction was stirred at 80° C. for 40 min, then poured into 350 mL of H2O. The aqueous mixture was extracted with diethyl ether (3×50 mL), then the combined ether layers were back extracted with H2O (2×50 mL), and brine (1×50 mL), dried over MgSO4, filtered, and concentrated in vacuo to furnish the titled compound as a colorless oil. MS (ESI) m/z=280 (M+H)+, 297 (M+NH4)+, 302 (M+Na)+: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.25 (d, J=7.5 Hz, 3 H) 1.37 (s, 9 H) 4.06 (m, 1 H) 5.07 (d, J=12.9 Hz, 1 H) 5.15 (d, J=12.5 Hz, 1 H) 7.34 (m, 6 H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][CH2:8][C:9]([O:11]CC)=O.C(N(CC)CC)C>C(O)C>[NH:1]1[C:9](=[O:11])[CH2:8][NH:7][C@H:3]2[CH2:4][CH2:5][CH2:6][C@H:2]12
Reactant: CCOC(=O)CN[C@H]1CCC[C@@H]1N
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1CN[C@H]2CCC[C@@H]2N1
Temperature: 85 °C

Procedure:
Ethyl N-[(1S,2S)-2-aminocyclopentyl]glycinate (HCl salt) (708 mg, 3.18 mmol) was dissolved in ethanol (16 mL), and triethylamine (4.43 mL, 31.8 mmol) was added. The resulting mixture was stirred and heated at 85° C. for 24 hours. The mixture was then cooled and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the resulting slurry was filtered. The filtrate was concentrated under reduced pressure to afford (4aS,7aS)-octahydro-2H-cyclopenta[b]pyrazin-2-one, which was used without further purification. 1H NMR (500 MHz, CDCl3) δ 6.31 (s, 1H), 3.68-3.67 (m, 2H), 3.23-3.17 (m, 1H), 2.86-2.81 (m, 1H), 1.97-1.82 (m, 5H), 1.49-1.40 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.[F:51][C@@H]1CCNC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][C@@H:24]([F:51])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: F[C@@H]1CCNC1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2CC[C@@H](F)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)-3-fluoropyrrolidine hydrochloride and isolated as light-yellow gum (9.8 mg, 54%). MS(m/e): 389.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=[O:14])[C:7](=[O:16])[CH2:6]2.[Cl:17][C:18]1[CH:19]=[N+:20]([O-:43])[CH:21]=[C:22]([Cl:42])[C:23]=1[CH2:24][C@@H:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[CH:28]=1)O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:17][C:18]1[CH:19]=[N+:20]([O-:43])[CH:21]=[C:22]([Cl:42])[C:23]=1[CH2:24][C@@H:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[CH:28]=1)[O:14][C:13](=[O:15])[CH2:12][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][C:7]1=[O:16]
Reactant: COc1ccc2c(c1)CC(=O)N2CC(=O)O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2c(c1)CC(=O)N2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Yield: 26.4 %

Procedure:
To a solution of 2-(5-methoxy-2-oxoindolin-1-yl)acetic acid (200 mg, 0.904 mmol) in DCM (30 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (380 mg, 0.904 mmol), EDC (520 mg, 2.71 mmol) and DMAP (55.2 mg, 0.452 mmol) were added, and the mixture was reacted at room temperature overnight. The solvent was evaporated, and the resulting crude was partitioned between DCM (20 ml) and a 1N HCl (20 ml), and the desired compound was extracted with ethyl acetate (3×20 ml). The combined organic layers were dried over sodium sulfate and the solvent was removed. The crude was purified by flash chromatography on silica gel (DCM:MeOH 98:2) recovering the title compound (149.2 mg, 0.239 mmol, 27% yield). MS/ESI+ 623.12 [MH]+; [αD]=+19.12 c=0.5 in DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.45 (s, 2H), 7.18 (d, 1H), 7.06 (d, 1H), 6.92-6.98 (m, 2H), 7.07 (t, 1H), 6.76 (dd, 1H), 6.64 (d, 1H), 6.02 (dd, 1H), 4.54 (d, 1H), 4.46 (d, 1H), 3.91 (d, 2H), 3.74 (s, 3H), 3.59 (s, 2H), 3.40 (dd, 1H), 3.21 (dd, 1H), 1.03-1.41 (m, 1H), 0.50-0.70 (m, 2H), 0.21-0.50 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[S:12](=[O:14])(=[O:13])[N:11](C(OC)=O)[CH2:10][C:9]2([CH3:20])[CH3:19])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:9]([CH3:20])([CH3:19])[CH2:10][NH:11][S:12]2(=[O:13])=[O:14])=[CH:5][CH:4]=1
Reactant: COC(=O)N1CC(C)(C)N(Cc2ccc(OC)cc2)S1(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(CN2C(C)(C)CNS2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
To a suspension of methyl 5-(4-methoxybenzyl)-4,4-dimethyl-1,2,5-thiadiazolidine-2-carboxylate 1,1-dioxide (17.56 g, 53.5 mmol) in methanol/water (300 mL, 2:1) was added 10 N NaOH (10.7 mL, 107 mmol) and the mixture stirred at room temperature for 4 h. The mixture was made acidic with 10 N HCl and washed with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and concentrated to give the title compound as a white solid (12.91 g, 89% yield). 1H NMR (500 MHz, CDCl3) δ: 7.34-7.32 (2H, m), 6.86-6.84 (2H, m), 4.74 (1H, brs), 4.18 (2H, s), 3.78 (3H, s), 3.24 (2H, s), 1.21 (9H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[CH2:12]Br.[CH2:14]([O:21][C:22](=[O:26])[NH:23][CH2:24][CH3:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+]>CN(C=O)C>[CH2:14]([O:21][C:22](=[O:26])[N:23]([CH2:12][C:3]1[CH:4]=[C:5]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:6]=[CH:7][C:2]=1[Br:1])[CH2:24][CH3:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCNC(=O)OCc1ccccc1
Reactant: CC(C)(O)c1ccc(Br)c(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(Cc1cc(C(C)(C)O)ccc1Br)C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To 2-(4-bromo-3-bromomethyl-phenyl)-propan-2-ol (0.255 g, 0.83 mmol) and ethyl-carbamic benzyl ester (0.446 g, 2.49 mmol) in DMF (15 mL) was added sodium hydride (60% in mineral oil; 0.103 g, 2.57 mmol), and the reaction was stirred for 30 minutes. The mixture was quenched with H2O and worked-up. The residue was purified by silica gel chromatography (0-40% EtOAc in hexanes) to give the title compound.