Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O:10][CH2:11][CH2:12][Cl:13])([O:6][CH2:7][CH2:8][Cl:9])[O:2]CCCl.[C:14]([C:18]1[C:19]([OH:28])=[C:20]([CH3:27])[C:21]([CH3:26])=[C:22]([CH:25]=1)[CH2:23]Cl)([CH3:17])([CH3:16])[CH3:15]>C1(C)C(C)=CC=CC=1>[C:14]([C:18]1[C:19]([OH:28])=[C:20]([CH3:27])[C:21]([CH3:26])=[C:22]([CH:25]=1)[CH2:23][P:1](=[O:2])([O:6][CH2:7][CH2:8][Cl:9])[O:10][CH2:11][CH2:12][Cl:13])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1c(CCl)cc(C(C)(C)C)c(O)c1C
Reactant: ClCCOP(OCCCl)OCCCl
Solvent: Cc1ccccc1C
Product: Cc1c(CP(=O)(OCCCl)OCCCl)cc(C(C)(C)C)c(O)c1C

Procedure:
13.45 tris-(2-chloroethyl) phosphite and 11.55 grams of the compound of Example 9 dissolved in 50 ml of dry xylene were mixed together and heated at 65° for 3 hours and then at 110° to 115° C for 2 1/2 hours during which 1,2-dichloroethane distilled out of the reaction mixture and was collected in a trap. The reaction mixture was freed of solvent at reduced pressure, the resulting solid was triturated with petroleum ether and then recrystallized successively from a solvent mixture of benzene-hexane and then from toluene, yielding the desired product as white crystals melting at 133° to 135° C (Compound 9).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[N:13]1([CH2:19][C:20]([OH:22])=O)[CH2:17][CH2:16][CH2:15][C:14]1=[O:18].[O:23]1[CH2:28][CH2:27][N:26]([C:29]([CH2:31][N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:30])[CH2:25][CH2:24]1>C(Cl)Cl>[N:13]1([CH2:19][C:20]([N:35]2[CH2:36][CH2:37][N:32]([CH2:31][C:29]([N:26]3[CH2:25][CH2:24][O:23][CH2:28][CH2:27]3)=[O:30])[CH2:33][CH2:34]2)=[O:22])[CH2:17][CH2:16][CH2:15][C:14]1=[O:18]
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: O=C(O)CN1CCCC1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(CN1CCN(C(=O)CN2CCCC2=O)CC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
CDI (2.43 g, 0.015 moles) was added to 1.72 g (0.012 moles) of (pyrrolidin-2-one-1-yl) acetic acid in 40 ml of CH2Cl2 under stirring and after one hour morpholinocarbonylmethyl piperazine 2.56 g, 0.012 moles) was added. The solution was kept under stirring for 20 hours at room temperature, the solvent was then evaporated and the residue chromatographed on silica gel using CHCl3 --MeOH as eluant, ratio 95:5.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:30]([OH:32])=O)[CH2:19][C:20]3[CH:28]=[C:27]([CH3:29])[C:23]4[NH:24][CH:25]=[N:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[CH2:66]([N:73]1[CH2:78][CH2:77][CH:76]([CH:79]2[CH2:84][CH2:83][NH:82][CH2:81][CH2:80]2)[CH2:75][CH2:74]1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:28]=[C:27]([CH3:29])[C:23]4[NH:24][CH:25]=[N:26][C:22]=4[CH:21]=3)[C:30]([N:82]3[CH2:81][CH2:80][CH:79]([CH:76]4[CH2:75][CH2:74][N:73]([CH2:66][C:67]5[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=5)[CH2:78][CH2:77]4)[CH2:84][CH2:83]3)=[O:32])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2nc[nH]c12
Reactant: c1ccc(CN2CCC(C3CCNCC3)CC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(Cc4ccccc4)CC3)CC2)cc2nc[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 120 mg (0.22 mmol) (R)-1-carboxy-2-(7-methyl-1H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 85 mg (0.27 mmol) TBTU and 50 μL (0.36 mmol) triethylamine in 10 mL THF and 1 mL DMF was stirred for 1 h at RT, then combined with 80 mg (0.31 mmol) 1-benzyl-[4,4′]bipiperidinyl and stirred overnight at RT. The reaction solution was combined with 1 mL saturated Na2CO3 solution and extracted with 100 mL EtOAc. The organic phase was dried over Na2SO4, filtered and evaporated down i.vac. The residue was purified via HPLC, the fractions containing the product were combined and evaporated to dryness i.vac.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10]
Reactant: OCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(C=O)ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)ccc1OCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
4-Hydroxy-3-methylbenzaldehyde (365 mg, 2.68 mmol), 3,4-dichlorobenzyl alcohol (665 mg, 3.76 mmol), and triphenylphosphine (980 mg, 3.74 mmol) were dissolved in tetrahydrofuran (8 mL), and a diethyl azodicarboxylate toluene solution (2.2 M, 1.71 mL, 3.76 mmol) was slowly added dropwise thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a white solid (542 mg, yield: 69%).
Reaction SMILES: [OH-].[Na+].CO.[CH3:5][C@@H:6]([CH:11]([C:17]([O:19]CC)=[O:18])[C:12]([O:14]CC)=[O:13])[CH2:7][CH2:8][CH2:9][CH3:10].Cl>O.CCOCC>[CH3:5][C@@H:6]([CH:11]([C:17]([OH:19])=[O:18])[C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCC[C@@H](C)C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: CCCC[C@@H](C)C(C(=O)O)C(=O)O
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
At room temperature, 81 g of sodium hydroxide (2 mol) were dissolved in 360 ml of water and 160 ml of methanol in a three-neck flask with internal thermometer, dropping funnel and stirrer. 124 g of diethyl [(R)-1-methylpentyl]malonate (0.51 mol) were then added. The mixture was heated to 70° C. and stirred at this temperature for 3.5 h, in the course of which a solid formed. After cooling to 25° C., the suspension was admixed with 250 ml of ether and, with cooling, with 400 ml of 20% by weight hydrochloric acid. After phase separation, the aqueous phase was extracted twice with 100 ml of ether. The combined organic phases were washed with 100 ml of water and then dried over sodium sulfate. After solvent had been distilled off, [(R)-1-methylpentyl]malonic acid was obtained in a yield of 85 g (89% of theory) (m.p.: 123° C.).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH2:13][OH:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH:17]1([N:20]2[C:24](S(C)(=O)=O)=[N:23][N:22]=[C:21]2[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH2:19][CH2:18]1>>[CH:17]1([N:20]2[C:24]([O:14][CH2:13][C:10]3[N:11]=[N:12][N:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=4)[N:9]=3)=[N:23][N:22]=[C:21]2[C:29]2[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=2)[CH2:19][CH2:18]1
Reactant: OCc1nnn(-c2cccc(I)c2)n1
Reactant: CS(=O)(=O)c1nnc(-c2ccncc2)n1C1CC1
Agent: [H-]
Agent: [Na+]
Product: Ic1cccc(-n2nnc(COc3nnc(-c4ccncc4)n3C3CC3)n2)c1

Procedure:
The title compound is prepared from [2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-methanol (1 mmol), sodium hydride (1.5 mmol) and 4-(4-cyclopropyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)-pyridine (1.25 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:9]1[C:10]([C:16](O)=[O:17])=[N:11][C:12]([CH3:15])=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=1>>[C:1]([O:5][C:6](=[O:7])[N:8]([C:9]1[C:10]([C:16](=[O:17])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=2)=[N:11][C:12]([CH3:15])=[CH:13][N:14]=1)[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cnc(N(C(=O)OC(C)(C)C)c2cccnc2)c(C(=O)O)n1
Reactant: Nc1ccc(F)cn1
Product: Cc1cnc(N(C(=O)OC(C)(C)C)c2cccnc2)c(C(=O)Nc2ccc(F)cn2)n1

Procedure:
The title compound, MS: m/e=425.2 (M+H+), was prepared in accordance with the general method of example 8, step 3 from 3-(tert-butoxycarbonyl-pyridin-3-yl-amino)-6-methyl-pyrazine-2-carboxylic acid and 2-amino-5-fluoropyridine.
Reaction SMILES: [CH3:1][O:2][N:3]([C:31]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:4]1[NH:5][C:6](=[O:30])[C:7]2[N:8]=[CH:9][N:10]([C@@H:13]3[O:17][C@H:16]([CH2:18][O:19][Si](C(C)(C)C)(C)C)[CH2:15][C@:14]3([C:28]#[CH:29])[F:27])[C:11]=2[N:12]=1.[F-].[NH4+]>CO>[CH3:1][O:2][N:3]([C:31]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:4]1[NH:5][C:6](=[O:30])[C:7]2[N:8]=[CH:9][N:10]([C@@H:13]3[O:17][C@H:16]([CH2:18][OH:19])[CH2:15][C@:14]3([C:28]#[CH:29])[F:27])[C:11]=2[N:12]=1
Reactant: C#C[C@]1(F)C[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]1n1cnc2c(=O)[nH]c(N(OC)C(c3ccccc3)(c3ccccc3)c3ccccc3)nc21
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: C#C[C@]1(F)C[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N(OC)C(c3ccccc3)(c3ccccc3)c3ccccc3)nc21
Temperature: 70 °C
Reaction time: 2 h

Procedure:
14 (0.35 mmol) was dissolved in MeOH (20 ml/mmol). Ammonium fluoride (3.55 mmol) was then added at room temperature and the reaction mixture was stirred at 70° C. for 2 hours. After concentration under reduced pressure, the crude material was purified by silica gel chromatography (DCM/MeOH) to yield the title compound. Beige foam. Molecular Formula C32H30FN5O4. 1H NMR (CDCl3-d6, 400 MHz) δ (ppm) 2.38-2.45 (m, 2H), 2.75 (brs, 2H), 3.64-3.67 (d, J=12.20 Hz, 2H), 3.77 (s, 4H), 4.20-4.23 (d, J=11.7 Hz, 1H), 4.41-4.42 (d, J=8.4 Hz, 1H), 5.83-5.87 (d, J=16.24 Hz, 1H), 6.80-6.82 (d, J=8.12 Hz, 4H), 7.26-7.31 (m, 11H), 7.84 (brs, 1H), 9.26 (brs, 1H)
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:42])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)[S:21]([C:24]1[CH:25]=[C:26]([CH2:30][C:31]([O:33]C)=[O:32])[CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:22].[OH-].[Li+].O1CCCC1>O>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:42])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)[S:21]([C:24]1[CH:25]=[C:26]([CH2:30][C:31]([OH:33])=[O:32])[CH:27]=[CH:28][CH:29]=1)(=[O:22])=[O:23]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CCN3CCCC3)S(=O)(=O)c3cccc(CC(=O)OC)c3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CCN3CCCC3)S(=O)(=O)c3cccc(CC(=O)O)c3)c2n1

Procedure:
The compound obtained in Example 2-13 (70 mg) and lithium hydroxide (20 mg) were added to tetrahydrofuran (4 ml) and water (2 ml) and by the same manner to Example 2-12, the titled compound was obtained as a white solid. Yield: 35 mg (51%); mp 192-193° C., MS APCI−ve 588 (M−H).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])[CH3:4].O1CCOCC1>C(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[O:5]
Reactant: BrBr
Reactant: CC(=O)c1ccco1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: O=C(CBr)c1ccco1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.3 %

Procedure:
Bromine (71.14 ml, 1.39 mol) is added dropwise over 1 hour to a solution of 117.59 g (1.07 mol) of 2-acetylfuran (1) in a mixture of 900 ml of either and 400 ml of 1,4-dioxane, at 0° C. under a nitrogen atmosphere. The reaction is warmed to ambient temperature and stirred for 18 hours, then quenched with 1.1 liter of saturated aqueous ammonium chloride and extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to give a dark oil. Flash-chromatography on neutral silica gel using chloroform as eluent followed by distillation using a Kugelruhr apparatus gives 190.81 g (94%) of compound 2 as a light yellow oil, boiling point 85° C. (0.30 mmHg).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].C(=O)([O-])[O-].[K+].[K+].[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][CH:23]=1)([O-:15])=[O:14].C(OCC)(=O)C>CN(C)C=O>[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[CH:24][CH:23]=1)([O-:15])=[O:14]
Reactant: CCCCCN
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCNCc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Yield: 76.8 %

Procedure:
n-Amylamine (0.54 g) and potassium carbonate (0.98 g) were suspended in dimethylformamide (3.5 mL), and [[2′-nitro-1,1′-biphenyl-4-yl]methyl] bromide (0.51 g) was added in portions. Four hours later, ethyl acetate (20 mL) was added, and the resulting mixture was washed once with water (40 mL) and twice with brine (90 mL, each). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column (chloroform/ethyl acetate) to afford N-[(2′-nitro-1,1′-biphenyl-4-yl)methyl]-N-pentylamine as a yellow oil (0.40 g). Yield: 77%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17]2[C:12](=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][C:9]1=[O:27]>ClC1C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17]2[C:12](=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[CH:11]=[CH:10][C:9]1=[O:27]
Reactant: COc1cc(-c2ccccc2Cl)c2c(c1)N(c1ccccc1Cl)C(=O)CC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: Clc1ccccc1
Product: COc1cc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2c1
Yield: 97 %

Procedure:
1,5-bis(2-chlorophenyl)-7-methoxy-3,4-dihydro-2(1H)-quinolinone (0.85 g, 2.134 mmol) and manganese dioxide (5 g) were heated in chlorobenzene (50 ml) under reflux for 17 h. After cooling, the chlorobenzene was removed in vacuo, ethyl acetate (80 ml) added to the residue, then filtered through celite. The filtrate was evaporated in vacuo to afford the title compound as a yellow solid (0.82 g, 97%)
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C:5](=[O:7])[NH:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.I[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu]I.O1CCOCC1>[CH3:1][C:2]1([CH3:14])[O:6][C:5](=[O:7])[N:4]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[C@H:3]1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: CC1(C)OC(=O)N[C@H]1c1ccccc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2C(=O)OC(C)(C)[C@@H]2c2ccccc2)cc1
Yield: 93 %

Procedure:
To a round bottom flask were added (S)-5,5-dimethyl-4-phenyloxazolidin-2-one (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (1.717 g, 8.98 mmol), methyl 4-iodobenzoate (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (2.353 g, 8.98 mmol), and dioxane (90 mL). Tribasic potassium phosphate (9.53 g, 44.9 mmol), and copper (I) iodide (1.710 g, 8.98 mmol) were then added to the flask. The vessel was purged with nitrogen and N,N′-dimethylethylenediamine (1.933 mL, 17.96 mmol) was added. The suspension was heated at reflux overnight yielding a tan suspension. The mixture was filtered through Celite® brand filter aid, and the filtrate was dried under reduced pressure providing (S)-methyl 4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)benzoate (2.72 g, 8.36 mmol, 93% yield) as a light green oil which was used in the next step. 1H NMR (400 MHz, CDCl3) δ=7.94-7.90 (m, 2H), 7.55-7.51 (m, 2H), 7.39-7.32 (m, 3H), 7.21-7.16 (m, 2H), 5.04 (s, 1H), 3.86 (s, 3H), 1.70 (s, 3H), 1.02 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][CH2:14][O:15][CH3:16].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:16][O:15][CH2:14][CH2:13][O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH2:1]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cccc([N+](=O)[O-])c1N

Procedure:
A solution of 5 g 2-Amino-3-nitro-phenol, 4.5 g 1-Bromo-2-methoxy-ethane, 4.4 g K2CO3 in 50 mL DMF were heated to 60° C. for 16 h. Then 50 mL of water were added and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over MgSO4, and the solvents were removed under reduced pressure. The remaining product was pure enough for the next reaction step. Yield: 5.8 g.
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]4[CH2:27][CH2:26][C:25]5[C:20](=[CH:21][C:22]([O:28][CH3:29])=[CH:23][CH:24]=5)[C@H:19]4O)[CH2:13][CH2:12]3)[C:10](=[O:31])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C.CCOCC>[CH3:29][O:28][C:22]1[CH:21]=[C:20]2[C:25]([CH2:26][CH2:27][C:18]([CH2:17][N:14]3[CH2:15][CH2:16][C:11]4([N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH2:8][NH:9][C:10]4=[O:31])[CH2:12][CH2:13]3)=[CH:19]2)=[CH:24][CH:23]=1
Reactant: COc1ccc2c(c1)[C@@H](O)[C@H](CN1CCC3(CC1)C(=O)NCN3c1ccccc1)CC2
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1ccc2c(c1)C=C(CN1CCC3(CC1)C(=O)NCN3c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.7 %

Procedure:
trans-1-Phenyl-8-[(1,2,3,4-tetrahydro-1-hydroxy-7-methoxy-2-naphthalenyl)methyl]-1,3,8-traizaspiro[4.5]decan-4-one (5.0 g, see example 196) is added in portions to 25 ml of 20% v/v sulfuric acid/acetic acid. The resulting mixture is stirred for 16 hours at room temperature protected from moisture by a drying tube. The reaction mixture is warmed on a steam bath for 5 minutes, cooled, poured onto ice, basified with solid sodium bicarbonate, and extracted with methylene chloride. The dried methylene chloride solution is concentrated to give a crude solid. Trituration with 1:1 absolute ethanol/ether yields 3.0 g of the title compound, melting point 184°-186° C.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:17]([NH:19][C@H:20]([C:33]([NH:35][C@H:36]([C:44]([N:46]1[CH2:57][CH2:56][CH2:55][C@H:47]1[C:48]([O:50]C(C)(C)C)=[O:49])=[O:45])[CH2:37][CH2:38][CH2:39][NH:40][C:41](=[NH:43])[NH2:42])=[O:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28]C(C)(C)C)=[CH:24][CH:23]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[CH3:58][C:59]([OH:61])=[O:60].[CH3:62][C:63]([OH:65])=[O:64].CC(O)=O>FC(F)(F)C(O)=O.C(S)C>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:17]([NH:19][C@H:20]([C:33]([NH:35][C@H:36]([C:44]([N:46]1[CH2:57][CH2:56][CH2:55][C@H:47]1[C:48]([OH:50])=[O:49])=[O:45])[CH2:37][CH2:38][CH2:39][NH:40][C:41](=[NH:42])[NH2:43])=[O:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[O:18])[CH:14]([CH3:15])[CH3:16])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9].[CH3:58][C:59]([OH:61])=[O:60].[CH3:62][C:63]([OH:65])=[O:64]
Reactant: CC(C)[C@H](NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CCS
Product: CC(C)[C@H](NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
670 mg of H-Arg-Val-Tyr(tBu)-Arg-Pro-OtBu triacetate are dissolved in a mixture of 10 ml of 90% trifluoroacetic acid and 1 ml of ethyl mercaptan. The solution is left to stand at room temperature for one hour, and is concentrated in vacuo. The residue is partitioned between water and tert.butyl methyl ether. The aqueous phase is stirred with a weakly basic ion exchanger (acetate form) until the pH has become 3.5-4.0. The ion exchanger is filtered off with suction, and the filtrate is freeze-dried.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][CH3:19])[CH:13]=2)[S:9][C:10]=1[CH3:11])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH2:18]([C:14]1[CH:13]=[C:12]([C:8]2[S:9][C:10]([CH3:11])=[C:6]([CH2:5][CH2:4][NH2:1])[N:7]=2)[CH:17]=[CH:16][N:15]=1)[CH3:19]
Reactant: CCc1cc(-c2nc(CCN=[N+]=[N-])c(C)s2)ccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCc1cc(-c2nc(CCN)c(C)s2)ccn1

Procedure:
The product was obtained starting from 4-(2-azidoethyl)-2-(2-ethylpyridin-4-yl)-5-methylthiazole (134 mg, 490 μmol) and triphenylphosphine polymer bound (248 mg, 735 μmol) according to the method described in example 46, step 3 as yellow oil (117 mg, 473 μmol, 96.5%).
Reaction SMILES: C[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:16]#[C:17]CO)[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]=1C.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH:3]1[C:4]2[C:13](=[CH:12][C:11]3[C:6]([C:5]=2[C:16]#[CH:17])=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:14]=[CH:15][CH:2]=1
Reactant: Cc1ccc2cc3ccccc3c(C#CCO)c2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C#Cc1c2ccccc2cc2ccccc12
Temperature: 120 °C
Yield: 30.7 %

Procedure:
1.3 g (5 mmol) of Dimethylhydroxymethyl-9-anthrylacetylene and 210 mg (5.25 mmol) of NaOH (KISHIDA CHEMICAL CO., Ltd., 0.7 mm granular, 98%) were placed in a 50 mL two-neck flask equipped with a reflux condenser and the air inside the flask was replaced with Ar. 25 mL of toluene was added thereto and the mixture was refluxed at 120° C. for 0.75 hour. Toluene was added to the reaction mixture and the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure by an evaporator. The crude reaction product was purified by column chromatography (Hexane/AcOEt=10/1) using silica gel to give 9-anthryl ethyne as an orange-color solid (0.31 g, yield: 31%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[N:22]=[CH:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=4)[N:19]=3)=[O:17])[C:12]([CH3:31])([CH3:30])[CH2:11]2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[O:32]1[CH2:37][CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH2:34][CH2:33]1.C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CO>[Cl:29][C:25]1[CH:24]=[C:23]([N:20]2[CH:21]=[N:22][C:18]([C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([C:35]5[CH2:36][CH2:37][O:32][CH2:33][CH:34]=5)[N:7]=4)=[O:9])[CH2:11][C:12]3([CH3:31])[CH3:30])=[O:17])=[N:19]2)[CH:28]=[CH:27][CH:26]=1
Reactant: CC1(C)CN(C(=O)c2cccc(Br)n2)CCN1C(=O)c1ncn(-c2cccc(Cl)c2)n1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(C)CN(C(=O)c2cccc(C3=CCOCC3)n2)CCN1C(=O)c1ncn(-c2cccc(Cl)c2)n1
Temperature: 140 °C
Reaction time: 0.25 h

Procedure:
A mixture of 500 mg (0.10 mmol) [4-(6-bromo-pyridine-2-carbonyl)-2,2-dimethyl-piperazin-1-yl]-[1-(3-chloro-phenyl)-1H-[1,2,4]triazol-3-yl]-methanone, 28 mg (0.13 mmol) 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester, 16 mg (0.020 mmol) [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with DCM (1:1) and 0.10 mL 5M aqueous potassium carbonate solution in 1.0 mL dioxane and 0.50 mL MeOH was stirred at 140° C. for 15 min under microwave irradiation. The reaction mixture was filtered through Alox (alkaline) and purified by HPLC.