Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[NH:15][S:16]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22])(=[O:18])=[O:17])=[O:4].CN1CCOCC1.[CH3:35][N:36]([CH3:42])[CH2:37][CH2:38][CH2:39][NH:40][CH3:41].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH3:35][N:36]([CH3:42])[CH2:37][CH2:38][CH2:39][N:40]([CH3:41])[C:21]([C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[S:16]([NH:15][C:6]1[CH:7]=[CH:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[C:3]([O:2][CH3:1])=[O:4])(=[O:18])=[O:17])=[O:22]
Reactant: CNCCCN(C)C
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2C(=O)O)ccc2ccccc12
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2C(=O)N(C)CCCN(C)C)ccc2ccccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of Example 149B (102 mg, 0.264 mmol) in dichloromethane (1.0 mL) was treated with 4-methylmorpholine (87 μL, 0.792 mmol), 4-dimethylaminopyridine (3 mg, 0.025 mmol), N,N,N′,-trimethyl-1,3-propanediamine (42.6 μL, 0.290 mmol), and bromotripyrrolidinophosphonium hexafluorophosphate (123.3 mg, 0.265 mmol), stirred at room temperature for 3 days, and treated with 1N HCl. The aqueous layer was extracted with ethyl acetate three times and the combined organic phases were washed with brine, dried (MgSO4), filtered, and concentrated. The resulting residue was purified by preparative HPLC to provide the desired product. MS (ESI(+)) m/e 484 (M+H)+; (ESI(−)) m/e 482 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 9.49 (s, 1H), 9.26 (s, 1H), 8.02 (d, 1H), 7.94 (dd, 1H), 7.1 (dd, 1H), 7.72 (dt, 1H), 7.61-7.48 (m, 5H), 3.84 (s, 3H), 3.19 (br s, 2H), 3.07 (m, 2H), 2.82 (d, 6H), 2.67 (s, 3H), 1.98 (quint, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:18])[CH2:16][CH3:17])[C:11]([OH:13])=O)[C:7](=[O:19])[CH:6]=1.[CH3:24][C:25]1([CH3:37])[O:29][C@H:28]([CH2:30][N:31]2[CH:35]=[CH:34][C:33]([NH2:36])=[N:32]2)[CH2:27][O:26]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:24][C:25]1([CH3:37])[O:29][C@H:28]([CH2:30][N:31]2[CH:35]=[CH:34][C:33]([NH:36][C:11](=[O:13])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=4[Cl:1])=[CH:6][C:7]3=[O:19])[CH2:14][CH:15]([CH3:18])[CH2:16][CH3:17])=[N:32]2)[CH2:27][O:26]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CCC(C)C[C@@H](C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.4 %

Procedure:
A solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-hexanoic acid (337 mg, 1 mmol), 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 276 mg, 1.4 mmol) in N,N-dimethylformamide (7 mL) was treated with N,N-diisopropylethylamine (0.46 mL) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (664 mg, 1.5 mmol) and stirred at room temperature for 6 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and an aqueous ammonium chloride solution. The layers were separated and the organic layer washed with brine and dried with sodium sulfate. The mixture was filtered and the filterate concentrated in vacuo and the residue was purified by ISCO flash chromatography (RediSep silica column 40 g, 20% to 80% ethyl acetate/hexanes) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-hexanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (400 mg, 76%) as a pale yellow solid: HR-ES-MS (m/z) calculated for C26H33ClN4O5 [M+H]+ 517.2212, observed 517.2209. 1H NMR showed mixture of diastereomers (300 MHz, DMSO-d6) δ ppm 0.75-0.95 (m, 6H), 1.02-1.23 (m, 2H), 1.25 (s, 3H), 1.31 (s, 3H), 1.40-1.93 (m, 3H), 3.73 (dd, J=8.5, 5.7 Hz, 1H), 4.00 (dd, J=8.3, 6.5 Hz, 1H), 4.04-4.28 (m, 3H), 4.35 (quin, J=5.7 Hz, 1H), 4.60 (dd, J=18.4, 14.5 Hz, 1H), 4.80 (2×s, 1H), 4.86-4.96 (m, 1H), 6.42-6.46 (m, 1H), 7.37 (t, J=7.5 Hz, 1H), 7.42-7.57 (m, 2H), 7.60 (s, 1H), 7.65 (d, J=7.8 Hz, 1H), 10.76-10.84 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2ncccc2Cl)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2ncccc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
0.64 g of 5-(4-chlorophenyl)-4-(3-chloro-2-pyridyl)-6-methyl-2H-pyrida zin-3-one and 15 g of phosphorus oxychloride were mixed. The mixture was stirred for 6 hours under reflux with heating. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.67 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.50 g of 3-chloro-5-(4-chlorophenyl)-4-(3-chloro-2-pyridyl)-6-methylpyridazine (hereinafter, described as compound (5) of the present invention.).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)=[CH:5][CH:4]=[N:3]1.CCN(C(C)C)C(C)C.Cl.[NH:25]1[C@@H:34]2[C@@H:29]([CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.O>[CH3:1][N:2]1[C:6]([C:7]2[S:11][CH:10]=[C:9]([C:12]([N:25]3[CH:34]4[CH:29]([CH2:30][CH2:31][CH2:32][CH2:33]4)[CH2:28][CH2:27][CH2:26]3)=[O:14])[CH:8]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1-c1cc(C(=O)O)cs1
Reactant: C1CC[C@@H]2NCCC[C@@H]2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1nccc1-c1cc(C(=O)N2CCCC3CCCCC32)cs1
Reaction time: 8 h
Yield: 76.6 %

Procedure:
5-(2-Methyl-2H-pyrazol-3-yl)-thiophene-3-carboxylic acid (0.084 g, 0.40 mmol) was dissolved in THF (2 mL) then DIPEA (0.22 mL, 1.3 mmol) and cis-decahydro-quinoline hydrochloride (DHQ [CIS-S]) (0.084 g, 0.48 mmol) were added followed by HATU (0.182 g, 0.48 mmol). The resulting mixture was stirred overnight then the mixture was diluted with water and extracted with DCM (×2). The organics were dried over sodium sulfate, filtered and evaporated. The crude material was purified by chromatography on a silica II cartridge, eluting with 50-100% ethyl acetate in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound as a colourless oil (0.101 g). LCMS m/z 330.19 [M+H]+ R.T.=10.43 min (Analytical Method 2).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][OH:34].CC1C=CC(CO)=CC=1>>[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][O:34][CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1
Reactant: OCc1cccc(Cl)c1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CCl)n1
Agent: Cc1ccc(CO)cc1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(COCc2cccc(Cl)c2)n1
Yield: 60 %

Procedure:
As described for Example 153, 4-[2-chloromethyl-1-(4-nitro-phenyl)-1H-imidazol-4-yl]-5-methyl-3-phenyl-isoxazole (100 mg, 0.25 mmol), using 3-chlorobenzyl alcohol and KI (8.4 mg, 0.05 mmol) instead of 4-methylbenzyl alcohol, was converted to the title compound (76 mg, 60%) which was obtained as a light yellow solid. MS: m/e=501.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:23](C)(C)C)=[CH:4][CH2:3]1.CC1C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC=2C(C)(C)CC=1>>[CH3:23][C:5]1[C:6]2[CH:7]=[C:8]([C:12]#[C:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)[CH:9]=[CH:10][C:11]=2[C:2]([CH3:1])([CH3:27])[CH2:3][CH:4]=1
Reactant: CC(C)(C)C1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Agent: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)=CCC3(C)C)cc1
Product: CC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoic acid (Compound 80), 33.7 mg (0.10 mmol) of ethyl 4-[(7,8-dihydro-5,8,8-trimethylnaphth-3-yl)ethynyl]benzoate (Compound 73) was converted into the title compound (colorless solid) using 10.2 mg (0.25 mmol) of LiOH in H2O.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][OH:11])=[C:6](Cl)[N:5]2[N:13]=[CH:14][CH:15]=[C:4]2[N:3]=1.C(N(CC)CC)C.[CH3:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1>C(O)(C)C>[Cl:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][OH:11])=[C:6]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:24][CH3:23])=[CH:27][CH:28]=2)[N:5]2[N:13]=[CH:14][CH:15]=[C:4]2[N:3]=1
Reactant: CCOc1ccc(N)cc1
Reactant: OCCCc1c(Cl)nc2ccnn2c1Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCOc1ccc(Nc2c(CCCO)c(Cl)nc3ccnn23)cc1
Temperature: 40 °C
Reaction time: 5 h
Yield: 67.2 %

Procedure:
To an isopropanol (3 mL) solution containing 3-(5,7-dichloropyrazolo[1,5-a]pyrimidin-6-yl)propan-1-ol (224 mg, 0.910 mmol), triethylamine (253 μL, 1.82 mmol) and phenethidine (128 μL, 1.00 mmol) were added, and this mixture was stirred at 40° C. for 5 hr. After the reaction, the solvent was distilled off, aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the filtrate was concentrated and the residue was purified with column chromatography (30% ethyl acetate-hexane) to obtain the title compound (212 mg).
Reaction SMILES: [CH2:1]([SH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.FC(F)(F)S([O-])(=O)=O.[F:37][C:38]([I+]C1C=CC=CC=1)([F:43])[C:39]([F:42])([F:41])[F:40]>C(Cl)Cl>[F:37][C:38]([F:43])([S:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:39]([F:42])([F:41])[F:40]
Reactant: CCCCCCCCCCCCS
Reactant: FC(F)(F)C(F)(F)[I+]c1ccccc1
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCCSC(F)(F)C(F)(F)F
Temperature: 25 °C

Procedure:
2.0 ml of methylene chloride, 0.10 ml (0.42 mmol) of 1-dodecanethiol and 87 mg (0.42 mmol) of 2,6-di-tert-butyl-4-methylpyridine were added to a flask, and 198 mg (0.42 mmol) of pentafluoroethylphenyliodonium trifluoromethanesulfonate was added thereto in small portions while stirring at room temperature, followed by stirring at room temperature for 20 minutes. The resulting white precipitate was filtered and subjected to column chromatography of silica gel. Iodobenzene and the product were eluted with pentane and purified by gas chromatography to obtain 1-pentafluoroethylthiododecane as an oily substance. Yield, 87%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13]Cl)[CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>CN(C)C=O>[CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13][N:18]([CH2:19][CH3:20])[CH2:16][CH3:17])[CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNCC
Reactant: O=C1CC(CCl)CN1Cc1ccccc1
Solvent: CN(C)C=O
Product: CCN(CC)CC1CC(=O)N(Cc2ccccc2)C1

Procedure:
A mixture of 14 g (0.06 mol) of crude 1-benzyl-4-chloromethyl-pyrrolidin-2-one, prepared as in Example 1(a), 10 g of diethylamine and 50 ml of dimethylformamide was stirred or shaken for 2 hours at 150° C. in an autoclave. The reaction mixture was evaporated to dryness in vacuo, the residue was taken up in methylene chloride, and the solution was washed first with water and finally the title compound was extracted twice with 25 ml of 2N HCl. The aqueous phase was separated, made alkaline with sodium hydroxide and the organic base was extracted with methylene chloride. The methylene chloride phase was evaporated, and the residue was distilled in vacuo.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:7][C:5]=2[CH:6]=1.[CH2:17](Br)[C:18]#[CH:19]>C(=O)([O-])[O-].[K+].[K+].CO>[CH2:19]([N:14]1[CH2:15][CH2:16][CH:11]([C:8]2[CH:9]=[CH:10][C:4]3[O:3][C:2]([CH3:1])=[CH:6][C:5]=3[CH:7]=2)[CH2:12][CH2:13]1)[C:18]#[CH:17]
Reactant: C#CCBr
Reactant: Cc1cc2cc(C3CCNCC3)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CCN1CCC(c2ccc3oc(C)cc3c2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.8 g (0.013 mol) of 4-(2-methyl-5-benzofuranyl)-piperidine (c.f. Example 12) and 2.4 g (0.02 mol) of 2-propynyl bromide are dissolved in a suspension of 10 g of potassium carbonate in 120 ml of methanol and the solution is stirred at room temperature. After 24 hours, a further 0.24 g of 2-propynyl bromide is added and the reaction mixture is stirred at room temperature for a further 24 hours. Thereafter, it is filtered, the residue on the filter is washed with ethyl acetate and the combined filtrates are evaporated to dryness under a waterpump vacuum. The residue is dissolved again in ethyl acetate and the solution is washed three times with water, dried over sodium sulfate and evaporated to dryness under a waterpump vacuum. The resulting residue is chromatographed on 200 g of aluminium oxide (eluting agent: methylene chloride), whereupon, after evaporating off the solvent, crystalline 1-(2-propynyl)-4-(2-methyl-5-benzofuranyl)-piperidine is obtained. The hydrochloride, prepared from the base in a conventional manner, melts at 185°-187°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:68]=[CH:67][C:13]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([C:45]4[CH:50]=[CH:49][C:48]([O:51][C:52]5[CH:57]=[CH:56][C:55]([N:58]=[N:59][C:60]6[CH:65]=[CH:64][C:63]([NH2:66])=[CH:62][CH:61]=6)=[CH:54][CH:53]=5)=[CH:47][CH:46]=4)([C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]5[CH:35]=[CH:34][C:33]([N:36]=[N:37][C:38]6[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=6)=[CH:32][CH:31]=5)=[CH:25][CH:24]=4)[CH3:22])=[CH:17][CH:16]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:69]1(=[O:79])O[C:72](=[O:73])[C:71]2=[CH:75][CH:76]=[CH:77][CH:78]=[C:70]12>C(O)(=O)C>[C:69]1(=[O:79])[N:66]([C:63]2[CH:64]=[CH:65][C:60]([N:59]=[N:58][C:55]3[CH:56]=[CH:57][C:52]([O:51][C:48]4[CH:49]=[CH:50][C:45]([C:21]([C:23]5[CH:24]=[CH:25][C:26]([O:29][C:30]6[CH:35]=[CH:34][C:33]([N:36]=[N:37][C:38]7[CH:43]=[CH:42][C:41]([N:44]8[C:69](=[O:79])[C:70]9=[CH:78][CH:77]=[CH:76][CH:75]=[C:71]9[C:72]8=[O:73])=[CH:40][CH:39]=7)=[CH:32][CH:31]=6)=[CH:27][CH:28]=5)([C:18]5[CH:19]=[CH:20][C:15]([O:14][C:13]6[CH:67]=[CH:68][C:10]([N:9]=[N:8][C:5]7[CH:4]=[CH:3][C:2]([N:1]8[C:72](=[O:73])[C:71]9=[CH:75][CH:76]=[CH:77][CH:78]=[C:70]9[C:69]8=[O:79])=[CH:7][CH:6]=7)=[CH:11][CH:12]=6)=[CH:16][CH:17]=5)[CH3:22])=[CH:46][CH:47]=4)=[CH:53][CH:54]=3)=[CH:61][CH:62]=2)[C:72](=[O:73])[C:71]2=[CH:75][CH:76]=[CH:77][CH:78]=[C:70]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(c1ccc(Oc2ccc(N=Nc3ccc(N)cc3)cc2)cc1)(c1ccc(Oc2ccc(N=Nc3ccc(N)cc3)cc2)cc1)c1ccc(Oc2ccc(N=Nc3ccc(N)cc3)cc2)cc1
Solvent: CC(=O)O
Product: CC(c1ccc(Oc2ccc(N=Nc3ccc(N4C(=O)c5ccccc5C4=O)cc3)cc2)cc1)(c1ccc(Oc2ccc(N=Nc3ccc(N4C(=O)c5ccccc5C4=O)cc3)cc2)cc1)c1ccc(Oc2ccc(N=Nc3ccc(N4C(=O)c5ccccc5C4=O)cc3)cc2)cc1
Temperature: 25 °C
Yield: 74.9 %

Procedure:
Into a 250 mL three-necked flask equipped with a magnetic stir bar and nitrogen inlet and outlet were placed 1,1,1-tris{4-[4-(4-aminophenyldiazenyl)phenoxy]phenyl}ethane (Example 5; 0.892 g, 1.00 mmol), phthalic anhydride (0,444 g, 3.00 mmol) and acetic acid (20 mL). The mixture was stirred under refluxing for 14 hours and allowed to cool to room temperature. The precipitate was collected by filtration and dried in an oven to afford 0.96 g (75%) of orange powder, mp >300° C. MS (m/e): 1282 (M+). Anal. Calcd. for C80H51N9O9: C, 74.93%; H, 4.01%; N, 9.83%. Found: C, 75.00%; H, 4.11%; N, 9.44%. 1H-NMR (d6-DMSO, δ in ppm): 2.21 (s, 3H, CCH3), 7.08-7.13 (d, 6H, Ar—H), 7.19-7.21 (dd, 12H, Ar—H), 7.67-7.71 (d, 6H, Ar—H), 7.87-8.03 (m, 24H, Ar—H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:12])([CH3:11])[C:6](OCC)=[O:7].[Li+].[BH4-].CO>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][OH:7]
Reactant: CCOC(=O)C(C)(C)CCCBr
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(CO)CCCBr
Yield: 108.1 %

Procedure:
According to the procedure given for the synthesis of 206e, 205a (94.0 g, 0.37 mol) was reduced with LiBH4 (12.97 g, 0.60 mol) and methanol (19.04 g, 0.60 mol) in CH2Cl2 (400 mL) to give 206a (78.0 g, 100%) as an oil. 1H NMR (DMSO-d6): δ 4.42 (s, 1H), 3.45 (t, 2H, J=6.6), 3.08 (s, 2H), 1.84-1.69 (m, 2H), 1.27 (t, 2H, J=8.3), 0.78 (s, 6H). 13C NMR (DMSO-d6): δ 69.7, 36.9, 35.7, 34.5, 27.4, 24.0.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]([O:11][C:12]([NH:14][C@@H:15]([C:19]([O-])=[O:20])[CH2:16][C:17]#[CH:18])=[O:13])([CH3:10])[CH3:9].C([O-])(O)=O.[Na+]>O1CCCC1.O>[C:8]([O:11][C:12](=[O:13])[NH:14][C@H:15]([CH2:16][C:17]#[CH:18])[CH2:19][OH:20])([CH3:10])([CH3:9])[CH3:7]
Reactant: C#CC[C@@H](NC(=O)OC(C)(C)C)C(=O)[O-]
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: C#CC[C@H](CO)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
An oven-dried, nitrogen-flushed 3-neck 500 mL round bottom flask equipped with a pressure-equalizing addition funnel was charged with LiAlH4 (1N in tetrahydrofuran, 46.9 ml, 46.9 mmol), and the flask was chilled in an ice-water bath. A solution of (R)—N-Boc-propargylglycine (5.0 g, 23.45 mmol) in tetrahydrofuran (100 ml) was then added dropwise through the funnel, controlling the addition so that the bubbling was not too vigorous. The reaction was allowed to come to room temperature and was stirred overnight, and chilled in an ice bath. Saturated aqueous NaHCO3 solution (15 mL) was added dropwise over about 0.5 hours. The resulting suspension was diluted with water (˜25 mL) and filtered through diatomaceous earth, rinsing with ether. The filtrate was transferred to a separatory funnel and the layers were separated. The organic phase was washed with saturated Rochelle's salt, water and brine then dried (Na2SO4), filtered and concentrated to give the title compound, which was used without further purification.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[NH:9][C:8]=1[C:18]([O:20]CC)=[O:19])(=[O:3])[CH3:2].O1CCCC1.[OH-].[Na+]>C(O)C>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[NH:9][C:8]=1[C:18]([OH:20])=[O:19])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc(OC)cc2c1CCNC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(C(=O)O)c(CCNC(C)=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a mixture of ethyl 3-(2-acetamidoethyl)-5-methoxy-1H-indole-2-carboxylate (350 mg), tetrahydrofuran (5.00 mL), and ethanol (5.00 mL) was added a 1 M aqueous sodium hydroxide solution (2.00 mL), followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in water and adjusted to be weakly acidic by the addition of 1 M hydrochloric acid. The precipitated solid was collected by filtration and then dried to obtain 3-(2-acetamidoethyl)-5-methoxy-1H-indole-2-carboxylic acid (300 mg) as a gray solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:4][N:3]=1.CN(C)CCN(C)C.C([Li])CCC.[Cl:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]=[O:42])=[CH:39][CH:38]=1>O1CCCC1.O>[Cl:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]([OH:42])[CH2:1][C:2]2[C:6]([C:7]3[CH:8]=[CH:9][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:11][CH:12]=3)=[C:5]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:4][N:3]=2)=[CH:39][CH:38]=1
Reactant: Cc1noc(-c2ccccc2)c1-c1ccc(S(N)(=O)=O)cc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2c(CC(O)c3ccc(Cl)cc3)noc2-c2ccccc2)cc1
Temperature: -40 °C
Yield: 45.3 %

Procedure:
To a cold (-70° C.) solution of 4-[3-methyl-5-phenylisoxazol-4-yl]benzenesulfonamide (Example 13) (250 mg, 0.8 mmol) and tetramethylethylenediamine (277 mg, 2.4 mmol) in tetrahydrofuran (5 mL) under an argon atmosphere was added n-butyllithium (1.3 mL of 1.84M in hexane, 2.4 mmol). The solution was warmed to -40° C. for 15 minutes, recooled to -70° C., and a solution of 4-chlorobenzaldehyde (337 mg, 2.4 mmol) in tetrahydrofuran (3 mL) was added. The mixture was warmed to room temperature over 30 minutes, poured into water (25 mL) and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The crude product was chromatographed on silica gel using mixtures of acetone and hexane as eluents to give 165 mg of desired product as a crystalline solid: mp 165°-167° C. Anal. Calc'd. for C23H19ClN2O4S(454.93): C, 60.72; H, 4.21; N, 6.16; S, 7.05. Found: C, 60.33; H, 4.34; N, 5.87; S, 6.74.
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)CC>[OH:1][CH:2]([CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)NCC2CO2)cc1
Reactant: C1CCNCC1
Solvent: CCCO
Product: O=[N+]([O-])c1ccc(S(=O)(=O)NCC(O)CN2CCCCC2)cc1
Yield: 90.1 %

Procedure:
4-[N-(2,3-Epoxypropyl)sulphamoyl]nitrobenzene (Method 116, 1 g, 3.88 mmol) and piperidine (0.34 g, 4 mmol) in 1-propanol (75 ml) were heated at reflux for 20 hours. The mixture was cooled and the solvent evaporated. The resulting yellow oil was triturated with diethyl ether collected by filtration and dried under vacuum to give the title compound 1.2 g (90%). NMR: 1.26-1.50 (m, 6H), 2.10-2.28 (m, 6H), 2.70 (dd, 1H), 2.90 (dd, 1H), 3.55 (m, 1H), 8.04 (d, 2H), 8.40 (d, 2H); m/z: 344.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](O)=[N:6][CH:7]=1.P(Br)(Br)([Br:12])=O>CN(C=O)C>[Br:12][C:5]1[C:4]([F:9])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: Oc1ncc(Cl)cc1F
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Product: Fc1cc(Cl)cnc1Br
Temperature: 130 °C
Yield: 73984.3 %

Procedure:
To solid 5-chloro-3-fluoro-2-hydroxypyridine (75 g, 0.51 mmol) was added melted POBr3 (150 g, 0.52 mmol). DMF (2 mL) was then added by pipet, and the mixture was heated at 130° C. for 1 h. The excess POBr3 was quenched by the careful addition of water to the reaction mixture at 0° C., and the resulting mixture was dissolved in a 2:1 mixture of EtOAc:water. The organic layer was washed three times with water and once with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting yellow oil was passed through a plug of silica gel (10% Et2O:90% hexanes) to provide the title compound as a white solid (79.4 g, 74%). The product was characterized by 1H NMR.