Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.[F:25][CH:26]([F:37])[O:27][C:28]1[CH:29]=[C:30]([S:34]([O-:36])=[O:35])[CH:31]=[CH:32][CH:33]=1.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[F:37][CH:26]([F:25])[O:27][C:28]1[CH:29]=[C:30]([S:34]([C:2]2[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([S:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)(=[O:16])=[O:15])[CH2:10][CH2:9]3)[CH:7]=2)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1
Reactant: O=S([O-])c1cccc(OC(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(c3cc(I)ccc3C)CC2)cc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCN(c3cc(S(=O)(=O)c4cccc(OC(F)F)c4)ccc3C)CC2)cc1
Yield: 63.1 %

Procedure:
0.521 g of 1-(5-Iodo-2-methyl-phenyl)-4-(toluene-4-sulfonyl)-piperazine (1.14 mmol), 0.315 g of sodium 3-(difluoromethoxy)benzenesulfinate (1.37 mmol), 0.558 g of cesium carbonate (1.713 mmol), 0.026 g of Pd(dba)3 (0.029 mmol), 0.033 g of Xantphos (0.059 mmol) and 0.381 g of tetrabutylammonium chloride (1.37 mmol) were stirred for 8 h in 10 mL of toluene. The reaction mixture was filtered and the solvent evaporated. The crude product was purified via silica gel chromatography with toluene/methanol 20:1 (2.5% triethylamine), fractions containing the product combined and the solvents evaporated to yield 0.386 g of product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:20]=[C:10]3[NH:11][C:12](=[O:19])[C:13]4[C:18]([N:9]3[N:8]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:2]1.I[CH:22]([CH3:24])[CH3:23].[H-].[Na+].O>O1CCOCC1>[CH:22]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:20]=[C:10]3[NH:11][C:12](=[O:19])[C:13]4[C:18]([N:9]3[N:8]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:2]1)([CH3:24])[CH3:23]
Reactant: CC(C)I
Reactant: O=c1[nH]c2cc(C3CCCNC3)nn2c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)N1CCCC(c2cc3[nH]c(=O)c4ccccc4n3n2)C1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 19 (0.07 g, 0.3 mmol) and 2-iodopropane (0.09 mL, 0.9 mmol) in dioxane (2 mL) and was treated with sodium hydride (0.01 g, 0.4 mmol). The mixture was stirred overnight at 65° C., cooled to ambient temperature, treated with water and concentrated. The residue was purified by flash chromatography on silica gel with 10% methanol/dichloromethane to provide the title compound. 1H NMR (CD3OD) δ 8.21 (dd, J=8.0, 1.5 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.81-7.87 (m, 1H), 7.42-7.47 (m, 1H), 5.88 (s, 1H), 3.21 (dt, J=11.3, 1.9, 1H), 2.99-3.10 (m, 2H), 2.92 (dt, J=13.2, 6.6 Hz, 1H), 2.51 (t, J=11.0 Hz, 1H), 2.38 (td, J=11.5, 2.8 Hz, 1H), 2.09 (ddd, J=9.0, 3.8, 3.7 Hz, 1H), 1.83-1.92 (m, 1H), 1.70-1.82 (m, 1H), 1.59 (qd, J=12.3, 4.0 Hz, 1H), 1.14-1.19 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[C:17]([O:21][C:22](=[O:39])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[C:25]([N+:36]([O-:38])=[O:37])[CH:24]=1)([CH3:20])([CH3:19])[CH3:18]>C(O)CCCC>[C:17]([O:21][C:22](=[O:39])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([C:4]3[N:3]=[C:2]([NH2:1])[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=3)[CH2:32][CH2:31]2)=[C:25]([N+:36]([O-:38])=[O:37])[CH:24]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCNCC2)c([N+](=O)[O-])c1
Solvent: CCCCCO
Product: COc1cc2nc(N3CCC(Nc4ccc(C(=O)OC(C)(C)C)cc4[N+](=O)[O-])CC3)nc(N)c2cc1OC
Temperature: 120 °C
Yield: 63.5 %

Procedure:
4-Amino-2-chloro-6,7-dimethoxyquinazoline (0.08 g, 0.33 mmol) was added to a solution of (44) (0.11 g, 0.35 mmol) in n-pentanol (5 mL) at 25° C. The mixture was heated to 120° C. and maintained at that temperature for 12 h. The reaction mixture was then cooled to room temperature and the desired product was filtered and rinsed with acetone to give 0.11 g (64%) of the title compound: TLC (Rf =0.30; 5% MeOH/CH2Cl2); 1H NMR (DMSO) δ 12.23 (s, 1H), 8.89 (s, 1H), 8.65 (s, 1H), 8.56 (s, 1H, J=2.0), 8.23 (d, 1H, J=7.8), 7.94 (d, 1H, J=9.2), 7.74 (s, 1H), 7.55 (s, 1H), 7.34 (d, 1H, J=9.3), 4.62 (d, 2H, J=13.3), 4.15 (m, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.35 (t, 2H, J=11.6), 2.10 (d, 2H, J=11.3), 1.74 (m, 2H), 1.53 (s, 9H); 13C NMR (DMSO) δ 163.5, 161.4, 155.2, 151.2, 146.8, 146.2, 136.3, 135.8, 130.6, 128.2, 117.9, 115.1, 104.9, 101.6, 99.1, 80.8, 56.2, 56.0, 48.8, 43.5, 30.5, 27.8; HRMS (FAB) m/z 525.2456 (M+H)+ (C26H32N6O6 requires 525.2454); Anal. (C26H32N6O6 ·1HCl) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:38])[C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:38])[C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:30][CH:29]=3)[CH:13]=2)[N:6]=1
Reactant: CC(C)(C)c1ccc(C(=O)NCCN=[N+]=[N-])cc1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)c3ccc(C(C)(C)C)cc3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.070 g, 0.253 mmol) was reacted with N-(2-azidoethyl)-4-tert-butylbenzamide (0.062 g, 0.253 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(4-tert-butylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.71 (d, 2H), δ 7.64 (t, 1H), δ 7.36 (d, 2H), δ 7.27 (s, 1H), δ 6.42 (s, 1H), δ 5.99 (s, 2H), δ 4.51 (t, 2H), δ 3.88 (q, 2H), δ 2.58 (t, 2H), δ 2.22 (t, 2H), δ 1.52 (m, 13H), δ 1.21 (m, 11H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.2, 155.3, 150.4, 149.6, 148.3, 138.9, 131.2, 127.3, 125.6, 122.2, 106.5, 84.8, 49.4, 40.2, 35.1, 31.3, 31.1, 29.3, 28.9, 28.3, 28.2, 28.1, 25.6 ppm; HRMS (ESI) calcd for C28H41N7O3(M+) 523.3271. Found 523.3270, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-4-tert-butylbenzamide hydrochloride (0.105 g, 90% yield). 1H NMR (400 MHz, CD3OD) δ 8.48 (s, 1H), δ 7.76 (d, 2H), δ 7.48 (d, 2H), δ 6.50 (s, 1H), δ 4.84 (s, 2H), δ 3.95 (s, 2H), δ 2.85 (s, 2H), δ 2.46 (t, 2H), δ 1.73 (s, 2H), δ 1.57 (m, 2H), δ 1.39 (s, 2H), δ 1.31 (s, 9H) ppm; 13C NMR (100 MHz, CD3OD) δ 169.2, 155.6, 147.3, 130.8, 129.9, 127.6, 127.2, 127.1, 126.7, 125.4, 125.3, 119.5, 108.6, 108.5, 52.3, 39.4, 34.6, 30.4, 27.9, 27.8, 27.6, 24.1, 23.2, 22.2 ppm; HRMS (ESI) calcd for C23H33N7O (M+) 423.2747. Found 423.2741.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])C)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH:20]3[CH2:21][CH2:23][CH2:13][CH:12]([CH3:17])[CH2:4]3)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1CCCC(Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.060 g, 0.13 mmol) in tetrahydrofuran (4 mL) and methanol (0.011 mL, 0.26 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.1 mL, 0.20 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid a pH of approximately 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 98:2 dichloromethane/methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.86 (m, 4 H) 1.08 (m, 1 H) 1.29 (m, 3 H) 1.60 (m, 3 H) 1.93 (m, 1 H) 3.04 (m, 1 H) 5.76 (d, J=3.31 Hz, 1 H) 7.14 (d, J=5.52 Hz, 1 H) 7.19 (d, J=8.46 Hz, 1 H) 7.26 (t, J=7.54 Hz, 1 H) 7.52 (dt, J=8.46, 1.47 Hz, 1 H) 7.65 (d, J=8.09 Hz, 1 H) 7.73 (t, J=5.15 Hz, 1 H) 15.93 (s, 1 H). MS (ESI−) m/z 457 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:20]4[C:15]3=[CH:16][CH:17]=[CH:18][CH:19]=4)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB(C2C=CC([C:41]3[CH:46]=[CH:45][C:44]([N:47]4[C:59]5[CH:58]=CC=C[C:54]=5C5C4=CC=CC=5)=[CH:43][CH:42]=3)=NC=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[CH:25]1[C:26]2[N:14]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[N:6]=[CH:7][C:2]([C:2]5[CH:7]=[N:6][C:5]([C:8]6[CH:13]=[CH:54][C:59]([N:47]7[C:44]8[CH:45]=[CH:46][CH:41]=[CH:42][C:43]=8[C:15]8[C:20]7=[CH:19][CH:18]=[CH:17][CH:16]=8)=[CH:58][CH:9]=6)=[CH:4][CH:3]=5)=[CH:3][CH:4]=4)=[CH:9][CH:10]=3)[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: CC1(C)OB(c2ccc(-c3ccc(-n4c5ccccc5c5ccccc54)cc3)nc2)OC1(C)C
Reactant: Brc1ccc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(c1)c1ccccc1n2-c1ccc(-c2ccc(-c3ccc(-c4ccc(-n5c6ccccc6c6ccccc65)cc4)nc3)cn2)cc1
Temperature: 80 °C
Yield: 180 %

Procedure:
A mixture of 6 (4.11 g, 10.3 mmol), 7 (4.60 g, 10.3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.595 g, 0.515 mmol), Na2CO3 (5.41 g, 51.0 mmol), H2O (55 mL) and THF (92 mL) was degassed with argon for about 1 h while stirring. The stirring reaction mixture was then maintained under argon at about 80° C. for about 18 h. Upon confirming consumption of the starting materials by TLC (SiO2, 49:1 dichloromethane-acetone), the reaction was cooled to RT, filtered and filtrant washed with EtOAc and H2O to afford 8 (5.92 g, 90%) as an off-white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([NH2:12])=[S:11])[CH2:6][CH2:5]1.[CH3:13][C:14]([C:17]([CH2:19]Br)=O)([CH3:16])[CH3:15].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[OH-].[Na+]>C(O)C>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][CH:19]=[C:17]([C:14]([CH3:16])([CH3:15])[CH3:13])[N:12]=2)[CH2:6][CH2:5]1
Reactant: CC(C)(C)C(=O)CBr
Reactant: NC(=S)N1CCN(CCO)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1csc(N2CCN(CCO)CC2)n1

Procedure:
5 g of 4-(2-hydroxyethyl)-1-piperazinyl-thiocarboxamide are added to a solution of 3.6 g of bromopinacoline in 70 cc of ethanol, and the reaction mixture is subsequently heated to the boil at reflux for 2 hours. The mixture is then concentrated by evaporation in a vacuum. The residue is dissolved in a small amount of water and is divided between chloroform and a concentrated aqueous sodium hydroxide solution. The chloroform phase is washed with water, dried over sodium sulphate and concentrated by evaporation in a vacuum. Hydrochloric acid in ethanol is added to the resulting oil and the solution is concentrated by evaporation. After recrystallizing the residue from a small amount of ethanol/diethyl ether, 2-[4-(2-hydroxyethyl)-1-piperazinyl]-4-tert.butyl-thiazole dihydrochloride, having a M.P. of 133°-142°, is obtained. The free base is obtained is known manner from the dihydrochloride by treatment with an aqueous sodium hydroxide solution.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]([OH:19])[CH:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:33](O)[CH2:34][CH2:35][OH:36].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[O:19][CH2:33][CH2:34][CH2:35][OH:36])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(Cl)c2)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a solution of 3-(3-chlorophenylsulfonyloxy)-5-methylphenol (450 mg, 1.5 mmol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol) and 1,3-propanediol (760 mg, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1'-(azodicarbonyl) dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (1:1 hexane/ethyl acetate) to give the title compound as a colorless oil (480 mg, 90%). 1H-NMR (300 MHz, CDCl3) δ 7.86 (s, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 6.64 (s, 1H), 6.41 (s, 1H), 6.37 (s, 1H), 4.01 (t, J=6.0 Hz, 2H), 3.82 (t, J=6.0 Hz, 2H), 2.25 (s, 3H), 1.99 (m, 2H), 1.65 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][C:14]([OH:16])=O)(=[O:11])=[O:10])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.Cl.[CH2:22]([O:24][C:25](=[O:29])[CH2:26][CH2:27][NH2:28])[CH3:23].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:22]([O:24][C:25](=[O:29])[CH2:26][CH2:27][NH:28][C:14](=[O:16])[CH2:13][CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:17]([F:20])([F:19])[F:18])[CH3:23]
Reactant: O=C(O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)CCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.152 g (10 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]propionic acid, 1.536 g (10 mmol) of β-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.Cl.[CH3:13][O:14][C:15](=[O:21])[C@H:16]1[CH2:20][CH2:19][CH2:18][NH:17]1.C(N(CC)CC)C>CC#N.O>[CH3:13][O:14][C:15]([C@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH2:10][C:5]1[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([Br:2])[CH:4]=1)=[O:21]
Reactant: COC(=O)[C@H]1CCCN1
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: COC(=O)[C@H]1CCCN1Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.3 %

Procedure:
A suspension of 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (8.00 g, 23.1 mmol) and D-proline methyl ester hydrochloride (4.53 g, 27.4 mmol) in CH3CN (100 mL) was treated with a solution of triethylamine (10.4 mL, 74.0 mmol) in CH3CN (100 mL). After stirring at room temperature for 5 h, the cloudy mixture was diluted with H2O (300 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 99:1 to 98:2) gave the title compound (6.55 g, 90%) as a colorless oil: MS (ESI) m/e 314 (M+H)+
Reaction SMILES: [C:1]([N@@:4]1[CH2:6][CH:5]1[CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])(=[O:3])[CH3:2].[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C=O)C.[Cl-].[Cl-].[Zn+2]>[CH2:9]([O:8][CH:7]([O:11][CH2:12][CH3:13])[C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][N:14]=[N+:15]=[N-:16])[CH3:10]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)C1CN1C(C)=O
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: CCOC(OCC)[C@@H](CN=[N+]=[N-])NC(C)=O
Temperature: 75 °C
Reaction time: 72 h
Yield: 62.9 %

Procedure:
A mixture containing 3.26 g of 124 and 15 g of sodium azide in 140 ml of DMF was added 140 ml of ZnCl2 (1.0M solution in Et2O). The mixture was stirred at 75° C. for 3 days and then extracted with EtOAc. The organic layer was washed with water, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (hexane/EtOAc=3:2) to yield 2.52 g of 125 (62%).
Reaction SMILES: C([O-])(=O)C.[CH2:5]([P+:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:6].O.O.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].C(O)(=O)C(O)=O>CO>[C:28]([O-:33])(=[O:32])[C:29]([O-:31])=[O:30].[CH2:5]([P+:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:6].[CH2:5]([P+:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:6]
Reactant: O=C(O)C(=O)O
Agent: CC(=O)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: O
Product: O=C([O-])C(=O)[O-]

Procedure:
To a 2 gallon bottle was charged 1000 g (1.707 mol) of a 70% methanol solution of ethyltriphenylphosphonium acetate.acetic acid complex followed by the addition of 204.4 g (1.622 mol) of oxalic acid dihydrate. The mixture was mixed until all the oxalic acid had dissolved and then about 31.5 g of methanol was added to give a resultant solution of about 50 wt. % ethyltriphenylphosphonium oxalate.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].[CH3:22][C:23]1[N:24]=[N:25][C:26]2[CH:27]=[CH:28][CH:29]=[C:30](N)[C:31]=2[CH:32]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:31]=1[CH:32]=[C:23]([CH3:22])[N:24]=[N:25]2)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Cc1cc2c(N)cccc2nn1
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cccc3nnc(C)cc23)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.5 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 66 mg (0.417 mmol) of 3-methylcinnolin-5-amine was added. The resulting mixture was stirred at room temperature for one day. The final product was collected by filtration and purified by column chromatography (silica gel, ethyl acetate/hexane 2:1) to yield the title compound (65 mg, 58.6% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.Cl.[NH2:14][OH:15].CC([O-])=O.[Na+]>CCO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[N:14][OH:15])[CH2:6][CH2:5]2
Reactant: NO
Reactant: O=C1CCc2cc(Br)ccc2C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCc2cc(Br)ccc2C1
Temperature: 25 °C

Procedure:
To a mixture of 6-bromo-3,4-dihydro-1H-naphthalen-2-one (5.370 g, 23.86 mmol) and hydroxylamine hydrochloride (2.487 g, 35.79 mmol) in EtOH (80 mL) was added a solution of NaOAc (5.871 g, 71.57 mmol) in H2O (20 mL). The mixture was heated to reflux for 2 h. The reaction was cooled to RT and concentrated in vacuo. The residue was suspended in H2O and filtered. The pad was washed with H2O (2×50 mL) and Et2O (2×50 mL) and the solids were dried in vacuo to furnish the title compound, which was used without further purification. MS (APCI pos) 242 (M+H).
Reaction SMILES: CC([Mg]Cl)C.[Br:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][N:8]=1.CN(C)[CH:16]=[CH:17][CH:18]=[O:19].Cl>C1COCC1>[Br:6][C:7]1[N:8]=[CH:9][C:10](/[CH:16]=[CH:17]/[CH:18]=[O:19])=[CH:11][CH:12]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CN(C)C=CC=O
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: O=C/C=C/c1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 25.9 %

Procedure:
2-Propylmagnesium chloride (2.0 M in THF, 5.00 mL 10.00 mmol) was added to a solution of 2,5-dibromopyridine (2.37 g, 10.00 mmol) in THF (5.0 mL) at RT. The resulting brown suspension was stirred for 1 h and then cooled to 0° C. 3-Dimethylaminoacrolein (95%, 1.30 mL, 12.36 mmol) was added and the mixture was warmed to RT and stirred for 2 h. 2 N HCl was added and after 5 min the mixture was cooled to 0° C. The precipitated solids were removed by filtration and partitioned between ethyl acetate (75 mL) and 10% NaOH (25 mL). The ethyl acetate layer was washed with brine (25 mL), dried (MgSO4), and concentrated. Recrystallization from ethyl acetate provided 550 mg (26%) of the title compound as shiny brown flakes. MS 211 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[Br:1])=[CH:14][CH:15]=1
Reactant: COc1ccc(CBr)cc1
Reactant: O=Cc1ccc(O)c(Br)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COc2ccc(C=O)cc2Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of 3-bromo-4-hydroxybenzaldehyde (5.0 g, 24.9 mmol; 1 eq) in DCM (10 mL), was added 1-(bromomethyl)-4-methoxybenzene (6.0 g, 29.88 mmol, 1.2 eq, Aldrich, Milwaukee, Wis., USA) and DIEA (8.7 mL, 49.7 mmol, 2 eq). After stirring at room temperature for 18 h, the reaction mixture was diluted with DCM and washed with saturated NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give 8.0 g of 4-(4-methoxybenzyloxy)-3-bromobenzaldehyde (32).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][OH:8])[N:6]=1.[Cl-].[NH4+].[CH2:11](N(CC)CC)[CH3:12]>[Cu](I)I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:11]([C:2]1[S:3][CH:4]=[C:5]([CH2:7][OH:8])[N:6]=1)#[CH:12]
Reactant: CCN(CC)CC
Reactant: OCc1csc(Br)n1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: [Cl-]
Product: C#Cc1nc(CO)cs1

Procedure:
2-bromo 4-thiazolyl methanol of preparation 39 was reacted with trimethylacetylene in the presence of copper iodide, bis(triphenylphosphine) palladium chloride and triethylamine and then the mixture was poured into an aqueous solution of ammonium chloride to obtain the expected alcohol.