Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH2:19][C:20](=[O:29])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([Br:18])=[CH:12][CH:11]=3>C1COCC1>[Br:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH2:19][C:20]([CH3:1])([OH:29])[CH2:21][O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([Br:18])=[CH:12][CH:11]=3
Reactant: C[Mg]Br
Reactant: O=C(COc1ccccc1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Solvent: C1CCOC1
Product: CC(O)(COc1ccccc1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Temperature: 0 °C
Yield: 89 %

Procedure:
Methylmagnesium bromide (92 μl, 3.0 M in THF) was added to an ice-cooled solution of title compound of example 103, step 1, 1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenoxypropan-2-one (86 mg, 0.18 mmol) in anhydrous THF (1.8 ml). The reaction was stirred in the gently warming ice bath for 6 hours, and then quenched by addition of water. The crude mixture was diluted with EtOAc and washed with saturated sodium bicarbonate, water and then brine. The organic layer was dried over Na2SO4, filtered and condensed. Some unreacted starting material was precipitated from ˜50% acetone/hexanes. The condensed filtrate was carried forward. Yield=89%. MS (ESI), m/z: calculated 486.98. found 531.7 (M+HCOO−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21](=[O:22])[C:12]3=[CH:13][NH:14][C:15]4[C:20]([N:11]3[C:10]2=[O:23])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:5][CH:4]=1.[Br:24]Br.C(O)(=O)C>O1CCOCC1.[Zn]>[Br:24][C:18]1[CH:19]=[C:20]2[C:15]([NH:14][CH:13]=[C:12]3[C:21](=[O:22])[N:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[C:10](=[O:23])[N:11]32)=[CH:16][CH:17]=1
Reactant: BrBr
Reactant: COc1ccc(-n2c(=O)c3c[nH]c4ccccc4n-3c2=O)cc1
Agent: [Zn]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1ccc(-n2c(=O)c3c[nH]c4ccc(Br)cc4n-3c2=O)cc1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 2-(4-Methoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (100 mg) in anhydrous dioxane(4 mL) was added bromine (200 mg). The reaction was stirred at 20° C. for 15 min, and was then poured directly into boiling acetic acid (50 mL) containing zinc powder (500 mg). The reaction was refluxed for 5 min and allowed to cool to room temperature. After dilution with 10% methanol/methylene chloride (100 mL), the mixture was filtered through silica gel the solvent was removed in vacuo, and the resulting solid was treated with boiling ethanol (25 mL) followed by dilution with water (100 mL). The mixture was cooled to 0° C. and the solid was filtered and dried to yield 8-Bromo-(4-methoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (Compound 26) as a yellow solid, m.p. 154° C. (dec).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([C:17]([O:19][CH3:20])=[O:18])=[CH:4][N:3]=1.[CH3:21][C:22]1[CH:45]=[CH:44][C:25]2[CH:26]([C:36]3[C:37](=[O:43])[NH:38][C:39](=[O:42])[NH:40][CH:41]=3)[C:27]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:28]=3[CH:29]=[CH:30][C:24]=2[CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:21][C:22]1[CH:45]=[CH:44][C:25]2[CH:26]([C:36]3[C:37](=[O:43])[NH:38][C:39](=[O:42])[N:40]([C:2]4[N:7]=[C:6]([NH:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([C:17]([O:19][CH3:20])=[O:18])=[CH:4][N:3]=4)[CH:41]=3)[C:27]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:28]=3[CH:29]=[CH:30][C:24]=2[CH:23]=1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Reactant: COC(=O)c1cnc(Cl)nc1NCC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(-n2cc(C3c4ccc(C)cc4C=Cc4cc(C)ccc43)c(=O)[nH]c2=O)nc1NCC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
A mixture of the product of step (ii) (0.52 g), the product of example 8 step (i) (0.5 g) and cesium carbonate (0.49 g) in dimethylformamide (15 ml) was heated at 70° C. After 3 hours, the reaction mixture was partitioned between 1M HCl and ethyl acetate. The organic phase was washed with water, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 3% methanol in chloroform. Yield 0.47 g.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][S:23]([CH3:22])(=[O:25])=[O:24])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCN
Product: CCCc1nc2cnc3ccccc3c2n1CCCCNS(C)(=O)=O
Yield: 48.1 %

Procedure:
Using the general method of Example 233 Part B except that the reaction was run at ambient temperature, 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine (2.00 g, 7.1 mmol) was reacted with methanesulfonyl chloride (1.65 mL, 21.3 mmol) to provide 1.23 g of N-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide as a light yellow solid, m.p. 133.2-134.6° C.
Reaction SMILES: [CH:1]1([C:4]2[NH:9][C:8]3[N:10]=[C:11]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[S:12][C:7]=3[C:6](=[O:19])[N:5]=2)[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[C:33]=1[CH3:42]>O1CCCC1>[CH:1]1([C:4]2[N:9]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:40])[F:41])[C:33]=3[CH3:42])[C:8]3[N:10]=[C:11]([N:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)[S:12][C:7]=3[C:6](=[O:19])[N:5]=2)[CH2:3][CH2:2]1
Reactant: O=c1nc(C2CC2)[nH]c2nc(N3CCOCC3)sc12
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cn2c(C3CC3)nc(=O)c3sc(N4CCOCC4)nc32)cccc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of 5-cyclopropyl-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (50 mg, 0.180 mmol) in Tetrahydrofuran (THF) (1000 μl) was stirred at 0° C. for 15 min, then lithium bis(trimethylsilyl)amide (359 μl, 0.359 mmol) in THF was added and stirring was continued for 30 min. 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (54.6 mg, 0.216 mmol) in Tetrahydrofuran (THF) (300 μl) was added and the mixture was stirred at 65° C. overnight. The reaction mixture was concentrated and the residue purified by reversed-phase HPLC to provide the major regio-isomer, 5-cyclopropyl-4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (Example 70). (9 mg, 11%); LC/MS: MS (ES+) m/e 451 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.83-0.92 (m, 2H), 0.98-1.07 (m, 2H), 1.86-1.97 (m, 1H), 2.51 (s, 3H), 3.45-3.56 (m, 4H), 3.63-3.73 (m, 4H), 5.76 (s, 2H), 6.92 (d, J=7.83 Hz, 1H), 7.37 (m, 1H), 7.64 (d, J=7.8 Hz, 1H).
Reaction SMILES: [C:1]1([CH3:50])[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH2:11][CH2:12][N:13]([S:40]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)(=[O:42])=[O:41])[CH2:14][CH2:15][N:16]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH2:17][CH2:18][NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:53][N:54]([CH2:58][CH2:59]Cl)[CH2:55][CH2:56]Cl>CN(C=O)C>[CH3:53][N:54]1[CH2:58][CH2:59][N:19]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:18][CH2:17][N:16]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:31])=[O:32])[CH2:15][CH2:14][N:13]([S:40]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)(=[O:41])=[O:42])[CH2:12][CH2:11][N:10]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:50])=[CH:2][CH:3]=2)(=[O:8])=[O:9])[CH2:56][CH2:55]1
Reactant: CN(CCCl)CCCl
Reactant: Cc1ccc(S(=O)(=O)NCCN(CCN(CCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCN(C)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a stirred solution of 1,4,7,10-tetra(p-toluenesulfonyl)-1,4,7,10-tetraazadecane prepared as in Example 15B (66.5 g, 0.0872 mole) in anhydrous DMF (1 l) was added sodium hydride (5.22 g--80% in mineral oil, 0.174 mole) in portions under a dry nitrogen blanket. The resulting mixture was stirred for 30 minutes under a dry argon atmosphere. The solution was then heated to 100° C. and a solution of N-methylbis(2-chloroethyl)amine freshly prepared as in Example 15A (13.6 g, 0.0872 mole) in anhydrous DMF (200 ml) was added dropwise over a 1.5 h period, maintaining the temperature at 100° C. After stirring an additional 45 minutes at 100° C., the solution was concentrated in vacuo to a volume of 750 ml. H2O was slowly added at room temperature to crystallize the product. The resulting brown solid was filtered, washed thoroughly with H2O and dried in vacuo over P2O5 to give 62.9 g (85% yield) of the crude product as a brown solid. The product was purified by crystallization from DMF-H2O to give a yellow solid: mp 170°-1° C.; 1H NMR (CDCl3) δ2.15 (s, 3 H), 2.43 (s, 6 H), 2.44 (s, 6 H), 2.51 (t, J=5.5 Hz, 4 H), 3.15 (t, J=5.5 Hz, 4 H), 3.29 (m, S H), 3.36 (s, 4 H), 7.32 (m, 8 H), 7.69 (m, 8 H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C@:8]([OH:58])([CH3:57])[C:9](=[O:56])[C@@H:10]([NH:15][C:16](=[O:55])[C@@H:17]([NH:25][C:26](=[O:54])[C@@H:27]([NH:32][C:33](=[O:53])[C@@H:34]([NH:43][C:44](=[O:52])[CH2:45][N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][CH:12]([CH3:14])[CH3:13]>>[CH3:1][S:2]([O:6][CH2:7][C@:8]([OH:58])([CH3:57])[C:9](=[O:56])[C@H:10]([CH2:11][CH:12]([CH3:13])[CH3:14])[NH:15][C:16](=[O:55])[C@H:17]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:25][C:26](=[O:54])[C@H:27]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH:32][C:33](=[O:53])[C@H:34]([CH2:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[NH:43][C:44](=[O:52])[CH2:45][N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)[C@](C)(O)CO
Product: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)[C@](C)(O)COS(C)(=O)=O

Procedure:
Prepared according to procedures described above, by reacting methanesulfonyl chloride with (S)—N—((S)-1-(((2R,4S)-1,2-dihydroxy-2,6-dimethyl-3-oxoheptan-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide. MS for C41H61N5O10S m/z: 816 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH2:17])=[S:16])=[CH:10][CH:9]=2)=[CH:6][N:7]=1)[CH3:2].Br[CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=O>C(O)C>[CH2:1]([C:3]1[O:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[S:16][C:27]4[CH2:28][CH2:29][CH2:30][CH:25]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:19][CH:20]=5)[C:26]=4[N:17]=3)=[CH:12][CH:13]=2)=[CH:6][N:7]=1)[CH3:2]
Reactant: O=C1C(Br)CCCC1c1ccccc1
Reactant: CCc1ncc(-c2ccc(NC(N)=S)cc2)o1
Solvent: CCO
Product: CCc1ncc(-c2ccc(Nc3nc4c(s3)CCCC4c3ccccc3)cc2)o1
Yield: 84.7 %

Procedure:
A solution of [4-(2-ethyl-oxazol-5-yl)-phenyl]-thiourea (124 mg, 0.50 mmol) and 2-bromo-6-phenyl-cyclohexanone (139 mg, 0.55 mmol) in ethanol (5 ml) was heated to reflux over night. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride and methylene chloride/methanol (19:1 v/v) as eluent to yield the title compound (170 mg, 85%) as a brown solid. MS ISP (m/e): 402.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.18 (br s, 1H, NH), 7.49 (s, 4H), 7.26-7.30 (m, 3H), 7.19 (t, 1H), 7.12 (d, 1H), 4.05 (m, 1H), 2.77 (q, 2H), 2.75 (m, 2H), 2.12 (m, 1H), 1.70-1.88 (m, 3H), 1.25 (t, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]([CH3:14])=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[CH3:15])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C=O)C>[Cl:19][C:9]([C:8]1[CH:12]=[C:13]([CH3:14])[C:5]([O:4][C:1](=[O:3])[CH3:2])=[C:6]([CH3:15])[CH:7]=1)=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Oc1c(C)cc(C(=O)O)cc1C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Oc1c(C)cc(C(=O)Cl)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound 3,5-dimethyl-4-hydroxybenzoic acid (5.04 g, 30.33 mmol) was mixed with pyridine (20 mL). Acetic anhydride (3.72 g, 36.4 mmol) was added and the mixture was stirred at room temperature for 4 h. The solvent was evaporated in vacuo to obtain 4-acetoxy-3,5-dimethyl-benzoic acid in quantitative yield (6.33 g). The compound 4-acetoxy-3,5-dimethyl-benzoic acid (0.36 g, 1.73 mmol)) was dissolved in dichloromethane (5 mL) and oxalyl chloride (0.3 mL, 3.46 mmol) was added dropwise, followed by 1 drop of DMF. The reaction mixture was stirred at room temperature under nitrogen for 2 h. The solvent was evaporated in vacuo to obtain acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester in quantitative yield (0.392 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:7]=12.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C)C=O>[CH2:26]([NH:33][C:11]([C:9]1[NH:8][C:7]2=[C:2]([Cl:1])[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=1)=[O:13])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cc2ccnc(Cl)c2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1cc2ccnc(Cl)c2[nH]1
Temperature: 50 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
A mixture of 7-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Reference Example 1) (0.10 g, 0.51 mmol) and 1,1′-carbonyldiimidazole (0.09 g, 0.53 mmol) in N,N-dimethylformamide (3.4 mL) was stirred at 50° C. for 1 h. To the stirring solution was added benzylamine (0.11 mL, 1.02 mmol) and the reaction mixture was stirred at 65° C. until the reaction was complete by TLC analysis. The crude reaction mixture was poured into rapidly stirring water, and extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×) and saturated NH4Cl, and dried over Na2SO4. The organic extract was filtered and concentrated to provide N-benzyl-7-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (0.04 g, 0.14 mmol, 27%) as an off-white solid: mp 217-220° C.; 1H NMR (300 MHz, CDCl3) δ4.70 (2H, d, J=5.7 Hz), 6.45-6.61 (1H, m), 6.85 (1H, s), 7.31-7.39 (5H, m), 7.47 (1H, d, J=5.7 Hz), 8.06 (1H, d, J=5.7 Hz), 9.55 (1H, br s); APCI MS m/z 286 [C15H12ClN3O+H]+; HPLC (Method A) >99% (AUC), tR=16.3 min.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.O.[NH2:27][NH2:28]>CO>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:5]([CH2:4][C:3]([NH:27][NH2:28])=[O:2])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)(=[O:15])=[O:14])=[CH:17][CH:18]=1)[CH3:24]
Reactant: NN
Reactant: CCOc1ccc(S(=O)(=O)N(CC(=O)OC)c2ccc(C)cc2)cc1
Solvent: CO
Solvent: O
Product: CCOc1ccc(S(=O)(=O)N(CC(=O)NN)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
The crude carboxylic acid methyl ester, e.g. methyl{[(4-ethoxyphenyl)sulfonyl]-4-methylanilino}acetate (3.816 g, 10.5 mmol), was dissolved in MeOH (30 mL). Hydrazine hydrate was added (3.3 mL). The reaction mixture was stirred overnight at room temperature. A white precipitate was formed. It was isolated by filtration and rinsed with cold MeOH. From mother liquors some more compound could be recovered, affording the desired product, e.g. 4-ethoxy-N-(2-hydrazino-2-oxoethyl)-N-(4-methylphenyl)benzenesulfonamide (2.745 g, 72%) as a colorless solid in 99.8% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].[Cl:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([N:16]=[C:17]=[O:18])=[O:15]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:17]([NH:16][C:14](=[O:15])[C:13]2[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=2[Cl:11])=[O:18])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10]
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: O=C=NC(=O)c1ccccc1Cl
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1ccccc1Cl)Nc1cc(Cl)c(O)c(Cl)c1
Temperature: 100 °C
Yield: 95.3 %

Procedure:
Into a reaction flask containing 6.23 grams (35.0 mmol) of 2,6-dichloro-4-aminophenol in 100 milliliters of toluene (heated to a temperature of 100° C. to dissolve the solid) was added with continuous stirring a solution of 7.63 grams (42.0 mmol) of 2-chlorobenzoyl isocyanate dissolved in 25 milliliters of toluene. The resulting exothermic reaction raised the temperature to boiling with the formation of a solid precipitate. Additional amounts of toluene were added to the reaction flask to facilitate stirring until the addition of 2-chlorobenzoyl isocyanate was complete. After cooling to ambient temperature, the solid precipitate was filtered and the residue was washed successively with toluene and hexane and air dried to afford 11.99 grams of 1-(3,5-dichloro-4-hydroxyphenyl)-3-(2-chlorobenzoyl)urea as a light brown solid having a melting point of 220° C.-222° C. Elemental analysis of the light brown solid indicated the following:
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9](OC)=[O:10])(=[O:5])=[O:4].[NH2:17][NH2:18]>CO>[NH:17]([C:9]([C:8]1[CH:7]=[C:6]([S:3]([N:2]([CH3:16])[CH3:1])(=[O:5])=[O:4])[CH:15]=[CH:14][CH:13]=1)=[O:10])[NH2:18]
Reactant: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1
Reactant: NN
Solvent: CO
Product: CN(C)S(=O)(=O)c1cccc(C(=O)NN)c1
Temperature: 65 °C
Yield: 40 %

Procedure:
Methyl 3-(N,N-dimethylsulfamoyl)benzoate (150 mg, 0.617 mmol) was added to hydrazine (29.6 mg, 0.925 mmol) in methanol (10 mL) and refluxed for 8 h at 65° C. Following cooling, the reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and the compound was purified by column chromatography affording the title compound (60 mg). 1H NMR (400 MHz, CDCl3): δ 8.11 (s, 1H), 8.01 (d, 1H, J=8.4 Hz), 7.92 (d, 1H, J=8.0 Hz), 7.65 (t, 1H, J=8.0 Hz), 2.73 (s, 6H). ESI-MS: 244.0 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([OH:6])[C:3]#[C:4][CH3:5].CC(C)([O-])C.[K+].Cl[C:14]1[N:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[N:18][CH:19]=1.Cl>CN(C=O)C.O>[CH3:1][CH:2]([O:6][C:14]1[N:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[N:18][CH:19]=1)[C:3]#[C:4][CH3:5]
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: CC#CC(C)O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CC(C)Oc1cnc(C(=O)O)cn1
Temperature: 75 °C
Yield: 65.3 %

Procedure:
50 ml RBF was charged with 3-pentyn-2-ol (2.063 ml, 22.08 mmol) in DMF (10 ml) and potassium t-butoxide (1.24 g, 11.04 mmol) was added portionwise while stirring (cooling in water bath). The mixture was stirred at room temperature for 10 min until all t-BuOK went into solution, then 5-chloropyrazine-2-carboxylic acid (500 mg, 3.15 mmol) was added in portions and the resulting brown suspension was heated at 75° C. for 45 min. The mixture was cooled to room temperature and diluted with water (˜20 ml) until all solids dissolved, then acidified with 2M HCl solution (˜5.5 ml) to pH 2. The resulting solution was extracted with EtOAc, organic layer was washed with water twice then with brine, filtered through pad of celite and concentrated in vacuo. The resulting suspension was diluted with 3 ml heptane/EtOAc (20:1) mixture then filtered. The solid was washed with heptane and dried in vacuo to afford 5-(pent-3-yn-2-yloxy)pyrazine-2-carboxylic acid (424 mg, 2.056 mmol, 65.2% yield) as tan solid. LC/MS (ESI+) m/z=207 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH3:10])[C:5](Cl)=[N:6][CH:7]=1.[NH2:12][NH2:13]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([CH3:10])=[N:13][NH:12][C:5]2=[N:6][CH:7]=1
Reactant: NN
Reactant: CC(=O)c1cc(Br)cnc1Cl
Product: Cc1n[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Starting material 1-(5-bromo-2-chloropyridin-3-yl)ethanone (5.8 g, 24.7 mmol) and 100 ml anhydrous hydrazine was charged into 500 ml round bottom flask and the resulting mixture was allowed to stir at room temperature for overnight. After removing the excess hydrazine via rotatory evaporation under reduced pressure, the remaining residue was diluted with distilled water and solid was appeared. After filtering the water, the resulting solid was taken up in ethylacetate and saturated aqueous sodium bicarbonate and was extracted by ethylacetate twice. The combined organic layer was washed with water and brine and dried over sodium sulfate. The crude product was eluted through a short silica gel column (3 inch in length) with ethylacetate as a white solid (4.0 g, y=77%).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([OH:22])=[CH:7][C:8]([C:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1.[ClH:33].[O:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][C:43](O)=[O:44])[CH2:36][CH2:35]1.C1(N=C=NC2CCCCC2)CCCCC1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.Cl>CCOCC.C(Cl)Cl>[ClH:33].[ClH:33].[CH3:32][C:2]1([CH3:1])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([O:22][C:43](=[O:44])[CH2:42][CH2:41][CH2:40][N:37]3[CH2:36][CH2:35][O:34][CH2:39][CH2:38]3)=[CH:7][C:8]([C:10]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCOCC1
Reactant: C#CCN1CCC2=C(C1)c1c(O)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CCOCC
Product: C#CCN1CCC2=C(C1)c1c(OC(=O)CCCN3CCOCC3)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.0 g. (10.1 mm.) of 5,5-dimethyl-10-hydroxy-8-(4-fluorophenyl-1-methylbutyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5H[1]benzopyrano[3,4-d]pyridine, 2.10 g. (10.1 mm.) of γ-morpholino-butyric acid hydrochloride and 2.18 g. (10.6 mm.) of dicyclohexylcarbodiimide are added to 200 ml. of methylene chloride. The reaction mixture is stirred at room temperature for 16 hours and after cooling, the by-product of dicyclohexylurea is removed by suction filtration. The mother liquor is evaporated to give a residue, which, after the usual workup, is converted to a dihydrochloride by the addition of an ether solution of hydrogen chloride. Recrystallization from methylene chloride/diethyl ether gives the final product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22](Cl)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[N:33]([CH3:37])[CH:34]=[CH:35][N:36]=1)CCC>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22]([C:32]4[N:33]([CH3:37])[CH:34]=[CH:35][N:36]=4)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Product: Cn1ccnc1-c1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1

Procedure:
Prepared according to Procedure B from 4-(4-benzyloxyanilino)-6-chloropyrido[3,4-d]pyrimidine and 2-(tri-n-butylstannyl)-N-methylimidazole (prepared according to the published method: J. Organometallic Chem., (1989), 61); δH [2H6]-DMSO 10.35 (1H,s), 9.17 (1H,s), 9.13 (1H,s), 8.65 (1H, s), 7.79 (2H,d), 7.32-7.55 (6H,m), 7.13 (1H,s), 7.09 (2H,d), 5.16 (2H,s), 4.10 (3H,s); m/z (M+1)+409.