Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)=[N:11][CH:10]=[N:9]2)[N:5]=[C:4]([CH3:24])[N:3]=1.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=1)#[CH:26]>C(#N)C.C(N(CC)CC)C.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.[Cu]I>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[O:20][CH3:21])[CH2:13][C:12]1[N:8]([C:6]2[CH:7]=[C:2]([C:26]#[C:25][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=3)[N:3]=[C:4]([CH3:24])[N:5]=2)[N:9]=[CH:10][N:11]=1
Reactant: COc1ccc(Cc2ncnn2-c2cc(Cl)nc(C)n2)cc1OC
Reactant: C#Cc1ccc(C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(Cc2ncnn2-c2cc(C#Cc3ccc(C)cn3)nc(C)n2)cc1OC
Temperature: 50 °C

Procedure:
A slurry of 4-chloro-6-(5-(3,4-dimethoxybenzyl)-1H-1,2,4-triazol-1-yl)-2-methylpyrimidine (1-3, 100 mg, 0.289 mmol, 1.0 eq), 2-ethynyl-5-methylpyridine (67.8 mg, 0.578 mmol, 2.0 eq), bis(triphenylphosphine)palladium(II) dichloride (10.15 mg, 0.014 mmol. 0.050 eq.) and copper(I) iodide (2.203 mg, 0.012 mmol 0.040 eq.) in a mixture of acetonitrile (1 ml) and triethylamine (1 mL) was heated at 50° C. for 16 h. The solvents were removed by roto-evaporation and the resulting residue was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to afford 4-(5-(3,4-dimethoxybenzyl)-1H-1,2,4-triazol-1-yl)-2-methyl-6-((5-methylpyridin-2-yl)ethynyl)pyrimidine (1-4). 1H NMR (500 MHz, CDCl3) δ 8.78 (s, 1H), 7.94 (m, 2H), 7.69 (m, 2H), 6.86 (m, 2H), 6.79 (d, 1H, J=8.2 Hz), 4.79 (s, 2H), 3.84 (s, 6H), 2.82 (s, 3H), 2.54 (s, 3H). HRMS m/z (M+H) 429.2029 found, 429.2034 required.
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([O:16][CH3:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)=[C:4]([O:16][CH3:17])[CH:3]=3)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: COc1cc(I)ccc1OCCN1CCCC1
Product: COc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
Prepared according to general working method I from 1-[2-(4-iodo-2-methoxy-phenoxy)-ethyl]-pyrrolidine (300 mg, 0.86 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (194 mg, 0.91 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=2)=[CH:8][CH:9]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Oc1ccc(Cc2ccc(Cl)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(Cl)cc2)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
To a solution of 4-(4-chloro-benzyl)-phenol (1.1 g, 5 mmol) in DMF (15 mL) at 0-5° C. was added 60% NaH (0.4 g, 10 mmol) at 0-5° C. The reaction mixture was stirred at rt for 15 min at 0-5° C. A solution of (R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.14 g, 6 mmol) in DMF (5 mL) was added to the above mixture at 0-5° C. The reaction mixture was warmed to rt and then heated at 90° C. for 15 h. The mixture was concentrated, diluted with saturated aq NaHCO3 and extracted with ethyl acetate. The aqueous layer was re-extracted with ethylacetate. The combined organic layers were dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (1.58 g, 78%).
Reaction SMILES: [OH-].[K+].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(=O)CCCCC1.[C:16](#[N:18])[CH3:17]>O>[C:5]1(=[CH:17][C:16]#[N:18])[CH2:4][CH2:3][CH2:8][CH2:7][CH2:6]1
Reactant: CCCCCC
Reactant: CC#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=C1CCCCC1
Product: N#CC=C1CCCCC1
Temperature: 55 °C

Procedure:
A 10 l round-bottom flask is loaded with 285 g (4.57 mols) of 90% potassium hydroxide in flakes and 1775 ml of hexane. The mixture is heated to 55° C. and, keeping heating, a solution consisting of 450 g (4.59 mols) of cyclohexanone and 1351 ml of acetonitrile is quickly dropped therein (during the addition temperature falls to 52.6° C.). The mixture is refluxed for 7 hours, then cooled at room temperature. 2863 ml of water are added thereof to dissolve the solid. The organic phase is washed twice with water (1000 ml each). The phases are separated and the organic phase is evaporated to dryness under vacuum, to obtain 462 g of a residue which is distilled under 10 mmHg at 100-105° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:15])[CH:10]2[NH2:14])[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:2].[Cl:19][CH2:20][C:21]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:22]=1[CH:23]([OH:27])[C:24](Cl)=[O:25]>C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:15])[CH:10]2[NH:14][C:24](=[O:25])[CH:23]([C:22]2[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:21]=2[CH2:20][Cl:19])[OH:27])[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:2]
Reactant: COc1ccc(C(O)C(=O)Cl)c(CCl)c1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(O)C(=O)NC2C(=O)N3C(C(=O)O)=C(COC(C)=O)CSC23)c(CCl)c1

Procedure:
A mixture of 1 g of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 1.2 g of 2-chloromethyl-4-methoxymandelic acid chloride in 200 ml of ethyl acetate is refluxed for 50 minutes after which the solvent is removed under high vacuum. The resulting product is chromatographed on silica gel using benzene-acetone as the eluant. The product obtained is triturated with ether to give 3-[(acetyloxy)methyl]-7-[[2-[2-(chloromethyl)-4-methoxyphenyl]-2-hydroxyacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. M.P. 140°-142° C (dec.).
Reaction SMILES: [CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([N:18]([C:76]2[N:81]=[C:80](Cl)[N:79]=[C:78]([NH:83][CH2:84][CH2:85][CH2:86][CH2:87][CH:88]3[CH2:93][C:92]([CH3:95])([CH3:94])[N:91]([O:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH3:104])[C:90]([CH3:106])([CH3:105])[CH2:89]3)[N:77]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH:57]2[CH2:62][C:61]([CH3:64])([CH3:63])[N:60]([O:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[C:59]([CH3:75])([CH3:74])[CH2:58]2)[C:26]2[N:31]=[C:30](Cl)[N:29]=[C:28]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]3[CH2:43][C:42]([CH3:45])([CH3:44])[N:41]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:40]([CH3:56])([CH3:55])[CH2:39]3)[N:27]=2)[CH2:12][C:11]1([CH3:108])[CH3:107])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:109][CH2:110][CH2:111][CH2:112][CH2:113][CH2:114][C:115]([O-:117])=[O:116].[Na+]>>[CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([N:18]([C:76]2[N:81]=[C:80]([NH:109][CH2:110][CH2:111][CH2:112][CH2:113][CH2:114][C:115]([OH:117])=[O:116])[N:79]=[C:78]([NH:83][CH2:84][CH2:85][CH2:86][CH2:87][CH:88]3[CH2:93][C:92]([CH3:95])([CH3:94])[N:91]([O:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH3:104])[C:90]([CH3:106])([CH3:105])[CH2:89]3)[N:77]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH:57]2[CH2:62][C:61]([CH3:64])([CH3:63])[N:60]([O:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[C:59]([CH3:75])([CH3:74])[CH2:58]2)[C:26]2[N:31]=[C:30]([NH:109][CH2:110][CH2:111][CH2:112][CH2:113][CH2:114][C:115]([OH:117])=[O:116])[N:29]=[C:28]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]3[CH2:43][C:42]([CH3:45])([CH3:44])[N:41]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:40]([CH3:56])([CH3:55])[CH2:39]3)[N:27]=2)[CH2:12][C:11]1([CH3:108])[CH3:107])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: NCCCCCC(=O)[O-]
Reactant: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(Cl)nc(N(CCCCCCN(c3nc(Cl)nc(NCCCCC4CC(C)(C)N(OCCCCCCCC)C(C)(C)C4)n3)C3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)C3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C
Agent: [Na+]
Product: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(NCCCCCC(=O)O)nc(N(CCCCCCN(c3nc(NCCCCCC(=O)O)nc(NCCCCC4CC(C)(C)N(OCCCCCCCC)C(C)(C)C4)n3)C3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)C3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of N,N'-bis(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)-N,N'-bis{2-chloro-4-[N-(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazin-6-yl}-1,6-hexanediamine and sodium 6-aminohexanoate.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[CH3:5][O:6][CH:7]([O:12][CH3:13])[CH2:8][CH2:9][CH2:10]Cl.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:5][O:6][CH:7]([O:12][CH3:13])[CH2:8][CH2:9][CH2:10][N:1]1[CH2:4][CH2:3][CH2:2]1
Reactant: COC(CCCCl)OC
Reactant: C1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCCN1CCC1)OC

Procedure:
A mixture of azetidine (2.0 g, 35.0 mmol), 4-chlorobutanal dimethylacetal (5.88 g, 39.0 mmol) and K2CO3 (5.38 g, 39.0 mmol), in anhydrous DMF (100ml), was stirred at room temperature for 72 h. Water (50 ml) was added and the mixture extracted with EtOAc (3×150 ml). The combined extracts were washed with H2O (3×50ml), dried (Na2SO4) and evaporated. The crude product was purified by distillation (1.2 g). δ (360 MHz, CDCl3) 1.35-1.42 (2H, m, CH2), 1.57-1.64 (2H, m, CH2), 2.00-2.40 (2H, m, CH2), 2.36 (2H, t, J=9.0 Hz, CH2), 3.15 (4H, m, t, J=7.0 Hz, 2 of CH2), 3.33 (6H, s, 2 of OMe), 4.35 (1H, t, J=5.7 Hz, CH).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]O)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=S)=[S:20].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35](Cl)=[O:36])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CC(C)=O.O>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]([S:20][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:12][CH:13]=2)=[O:36])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: S=C=S
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Reactant: OCc1ccc(OCc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)SCc2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
Under argon 84 mg (1.5 mmol) of solid KOH was dissolved at rt in 214 mg (1 mmol) 4-(benzyloxy)-benzyl alcohol and 0.5 ml acetone. Then 76 mg (1.1 mmol) carbon disulfide was added and the mixture thoroughly stirred for 2 h. 323 mg (1.3 mmol) 4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl ester was added and the mixture heated at reflux for 8 h. The reaction mixture was cooled to rt, 3 ml of water added and extracted with TBME. The organic phase was washed with water and brine to pH 7, dried over Na2SO4 and evaporated. Purification of the crude product by preparative HPLC on a PRO C18 column with a H2O/MeCN gradient provided 87 mg 4-(4-benzyloxy-benzylsulfanylcarbonyl)-piperazine-1-carboxylic acid tert-butyl ester as colourless powder. 1H-NMR (CDCl3): 1.46 s, 9H; 3.40–3.65 m, 8H; 4.13 s, 2H; 5.04 s, 2H; 6.90 d, 2H and 7.25–7.48 m, 7H.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11]O)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1C=CC(OP(OC2C=CC=CC=2)([N:22]=[N+:23]=[N-:24])=O)=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.C(Cl)Cl>[N:22]([CH2:11][C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][CH:2]=[N:1]2)=[CH:6][CH:7]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: OCc1ccc2cccnc2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: [N-]=[N+]=NCc1ccc2cccnc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of quinolin-7-ylmethanol (1.2 g, 7.2 mmol) and diphenylphosphonic azide (3.8 mL, 17 mmol) was dissolved in toluene (20 mL) and methylene chloride (6 mL). The mixture was cooled to 0° C. and neat 1,8-diazabicyclo[5.4.0]undec-7-ene (2.6 mL, 17 mmol) was added. The reaction was stirred for 30 minutes at 0° C. and then reacted at room temperature for 2 h. The mixture was diluted with CH2Cl2 (100 mL) and washed with water (100 mL×2). The organic layer was concentrated in vacuo and purified by silica gel chromatography (0-100% EtOAc/hexane) to afford a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][Cl:22]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][Cl:22])=[CH:5][CH:4]=1)#[N:2]
Reactant: ClCCCCCBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(OCCCCCCl)cc1

Procedure:
A stirred solution of 4-cyanophenol (80.9 g, 0.679 mol) in 1260 mL of acetonitile is treated with potassium carbonate (93.9 g, 0.679 tool) and 1-bromo-5-chloropentane (126 g, 0.679 mmol). The reaction is refluxed overnight and potassium carbonate is filtered off. The filtrate is concentrated in vacuo to generate oil which is partitioned between ether and water. The organic layer is washed with water, dried with magnesium sulfate, and concentrated in vacuo to afford 5-(4-cyanophenoxy)pentyl chloride as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.[CH3:12][NH2:13].[H][H]>CO.[Pd]>[CH3:11][C:4]1[N:3]=[C:2]([NH:13][CH3:12])[C:7]([NH2:8])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CN
Agent: [Pd]
Solvent: CO
Product: CNc1nc(C)ccc1N
Temperature: 25 °C
Yield: 83 %

Procedure:
2-Chloro-6-methyl-3-nitropyridine (2.5 g, 14.5 mmol) was stirred in 1.0 M solution of methylamine (40 ml, 40 mmol) in methanol at 70° C. for 60 min. After cooling to ambient temperature, and methanol (60 ml) and 10% palladium on activated carbon were added and the resulting mixture was shaken under 40 psi of hydrogen gas at ambient temperature for 30 min. The mixture was filtered through a pad of Celite and concentrated in vacuum. Chromatography on silica gel, eluting with a mixture dichloromethane-methanol-38% aqueous ammonia (9:1:0.1) yielded the title compound (1.65 g, 83%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C(O)C>[CH2:14]([O:5][C:4](=[O:6])[C:3]1[C:2]([OH:1])=[CH:10][CH:9]=[CH:8][C:7]=1[OH:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1c(O)cccc1O
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(OCc1ccccc1)c1c(O)cccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2,6-dihydroxybenzoic acid (500 mg, 3.24 mmol) in ethanol (8 mL) is added NaOH (130 mg, 3.24 mmol). After the mixture is stirred at RT for 3 h, the solvent is removed under reduced pressure. The resulting sodium salt is dissolved in DMF (10 mL) then benzyl bromide (0.39 mL, 3.24 mmol) is added and the mixture is stirred at RT for 18 h. Water is added and the mixture is extracted with EtOAc. The organic phase is washed with water and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using hexane/EtOAc (10:1) as eluent to give the title compound as an oil.
Reaction SMILES: [O:1]=[C:2]1[C:7]([O:8]CC2C=CC=CC=2)=[CH:6][NH:5][C:4]([C:16]([NH:18][N:19]2[CH2:23][CH2:22][N:21]([C:24]([NH:26][NH2:27])=[O:25])[C:20]2=[O:28])=[O:17])=[CH:3]1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[H][H]>C(#N)C.[Pd]>[OH:8][C:7]1[C:2](=[O:1])[CH:3]=[C:4]([C:16]([NH:18][N:19]2[CH2:23][CH2:22][N:21]([C:24]([NH:26][NH2:27])=[O:25])[C:20]2=[O:28])=[O:17])[NH:5][CH:6]=1
Reactant: [H][H]
Reactant: NNC(=O)N1CCN(NC(=O)c2cc(=O)c(OCc3ccccc3)c[nH]2)C1=O
Agent: [Pd]
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CC#N
Product: NNC(=O)N1CCN(NC(=O)c2cc(=O)c(O)c[nH]2)C1=O
Reaction time: 1 h
Yield: 52.4 %

Procedure:
3-[[[1,4-Dihydro-4-oxo-5-(phenylmethoxy)-2pyridinyl]carbonyl]amino]-2-oxo-1-imidazolidinecarboxylic acid, hydrazide (21.9 g) was suspended in 250 ml of acetonitrile. To the suspension was added 75 ml of bis-trimethylsilylacetamide and the mixture was stirred to form a solution. To the solution was added 10 g of palladium on charcoal (10%) and hydrogen was passed through the vigorously stirred mixture. The debenzylation was complete after 1 hour. After filtration, 15 ml of methanol and 10 drops of acetic acid were added to precipitate the title compound. Yield: 10.8 g. This crude material was stirred with 150 ml of ethanol to yield 8.8 g of the title compound, melting point <205° C., dec.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:24]([O:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccc(-c2ccccc2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
A solution of methyl 2-hydroxy-3-phenylbenzoate (9.5 g, 41.7 mmol) in DMF (80 ml) was treated with K2CO3 (8.6 g, 62.5 mmole) and benzyl bromide (10.6 g 62.2 mmol). The reaction was stirred at ambient temperature overnight, then partitioned between ethyl acetate/and water. The organic phase was washed well with water, dried (MgSO4) and evaporated. The residue was purified by chromatography (eluant: ethyl acetate/hexane) to give methyl 2-benzyloxy-3-phenylbenzoate (11.23 g, 8.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br-:14].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1>[Br:14][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(Cl)c([N+](=O)[O-])c1
Yield: 70.3 %

Procedure:
To a flask equipped with a magnetic stir bar and under an atmosphere of N2 was added 4′-chloro-3′-nitroacetophenone (10.0 g, 50.1 mmol) and THF (100 mL). To this stirring mixture was added portion-wise phenyltrimethylammonium tribromide (19.78 g, 52.6 mmol) over a 15 minutes time period. The resultant mixture was then stirred with monitoring every hour via LCMS. After 3 hr the mixture was then filtered and resulting solids washed with EtOAc. The organic solution was then concentrated, H2O and 10% aq. NaHCO3 added and washed with EtOAc (2×300 mL). The combined organic layers were then washed with Brine, dried (MgSO4), filtered and concentrated. The residue material was then subjected to purification via crystallization (dissolved material in 100 mL EtOAc and slowly added hexanes until cloudy—let stand for a few hours) to yield 9.81 g (70%) of 2-bromo-1-(4-chloro-3-nitrophenyl)ethanone as an off white colored solid product. 1H NMR (500 MHz, DMSO-D6) δ ppm 5.00 (s, 2H) 7.98 (d, J=8.54 Hz, 1H) 8.24 (dd, J=8.54, 2.14 Hz, 1H) 8.61 (d, J=1.98 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH:7][C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]([C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]=2)[S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])=[CH:4][C:3]=1[C:20]([F:23])([F:21])[F:22]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cn1c(NCc2ccc(F)c(C(F)(F)F)c2)nc2ccccc21
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cn1c(N(Cc2ccc(F)c(C(F)(F)F)c2)S(=O)(=O)c2ccccc2)nc2ccccc21
Temperature: 100 °C

Procedure:
To (4-fluoro-3-trifluoromethyl-benzyl)-(1-methyl-1H-benzimidazol-2-yl)-amine (195 mg, 0.6 mmol) in anhydrous pyridine (3 mL) at room temperature was added benzenesulfonyl chloride (193 mg, 1.1 mmol). The resulting mixture was heated to 100° C. in a microwave reactor for 1 h; then diluted with EtOAc, washed with 1 N HCl, the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2), eluting with a hexanes-EtOAc gradient to yield the title compound. MS 464 (M+1)+
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[C@@H:15]12[N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:19]([CH2:20][CH2:21]1)[CH2:18][NH:17][CH2:16]2.CCN(C(C)C)C(C)C>C(O)C>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:17]3[CH2:16][C@H:15]4[N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:19]([CH2:20][CH2:21]4)[CH2:18]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CNC2
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CN(c1ccc3nnc(C(F)(F)F)n3n1)C2
Yield: 68.8 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (312 mg, 1.40 mmol), (1R,5S)-tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (312 mg, 1.47 mmol) and DIPEA (0.36 ml, 2.10 mmol) in ethanol (7.00 ml) was heated at 70° C. for 18 hours. On cooling a white precipitate formed which was collected by filtration, washed with ethanol (10 mL) and dried under vacuum to afford (1R,5S)-tert-butyl 3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (384 mg, 69%) as a white crystalline solid.
Reaction SMILES: [CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[CH:20][C:19](=O)[O:18][C:17]=2[CH3:24])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.C(O)C.O.[NH2:29][NH2:30].C(O)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>>[CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[CH:20][C:19](=[O:18])[N:29]([NH2:30])[C:17]=2[CH3:24])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: Cc1cc(=O)oc(C)c1C(=O)N[C@H](c1cccc(F)c1)C1CCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Cc1cc(=O)n(N)c(C)c1C(=O)N[C@H](c1cccc(F)c1)C1CCC1
Temperature: 80 °C
Reaction time: 7 h
Yield: 33 %

Procedure:
To a solution of 2,4-dimethyl-6-oxo-6H-pyran-3-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide (419 mg, 1.27 mmol) in ethanol (4.0 mL, 70 mmol) were added hydrazine hydrate (370 uL, 7.6 mmol) and acetic acid (4.0 mL, 70 mmol). The mixture was heated at 80° C. for 24 hrs. More hydrazine hydrate (371 uL, 7.63 mmol) was added and stirring continued for 7 hrs. The reaction mixture was adjusted to neutral pH by addition of aq. Sat. Na2CO3. The crude mixture was extracted with dichloromethane (4×40 mL), combined organic phases were washed with brine, dried over MgSO4 and evaporated. The residue was purified by flash chromatography to give the title compound, yield 33%. LC-MS (m/z) 344.4 (MH+); tR=1.32 (method C). 1H NMR (600 MHz, CDCl3): 7.84 (d, J=8.6 Hz, 1H), 7.34 (td, J=7.9, 6.0 Hz, 1H), 7.20 (d, J=7.7 Hz, 1H), 7.17-7.11 (m, 1H), 6.99 (td, J=8.3, 2.0 Hz, 1H), 6.02 (s, 1H), 5.22 (s, 2H), 5.11-5.02 (m, 1H), 2.87-2.75 (m, 1H), 2.29 (s, 3H), 2.24 (m, 1H), 2.05 (s, 3H), 2.00-1.75 (m, 5H). 13C NMR (151 MHz, CDCl3) 166.34, 162.14, 159.96, 146.98, 143.64, 142.71, 130.10 (d, J=8.2 Hz, 1C), 122.78, 118.63, 114.34 (d, J=21.0 Hz, 1C), 114.14, 113.79 (d, J=21.6 Hz, 1C), 58.74, 40.05, 26.17, 25.59, 19.48, 17.49, 16.63.