Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[N:13][NH:14][C:15](=[O:16])[C:10]=2[CH:9]=[CH:8]1.C(=O)([O-])O.[Na+].S([O-])(O)=O.[Na+].[Cl-:29].[Na+]>C(OCC)(=O)C.C(#N)C>[Cl:29][C:9]1[C:10]2[C:15](=[O:16])[NH:14][N:13]=[CH:12][C:11]=2[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:18])([CH3:17])[CH3:1])[CH:8]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(=O)[nH]ncc21
Reactant: [Cl-]
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1cc(Cl)c2c(=O)[nH]ncc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 65 %

Procedure:
To 150 ml of acetonitrile solution containing 2.99 g (11.3 mmol) of 1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 16-(b) was added 1.42 g (10.6 mmol) of N-chlorosuccineimide, the mixture was stirred at room temperature for 3.5 hours, 0.53 g (4.0 mmol) of N-chlorosuccineimide was further added to the mixture and the resulting mixture was stirred for 24 hours. After completion of the reaction, to the reaction mixture were added a saturated aqueous solution of sodium hydrogencarbonate, 5% sodium hydrogen sulfite and ethyl acetate, and the mixture was stirred for 1 hour. Then, a saturated aqueous solution of sodium chloride was added to the solution and the liquids were separated. The organic layer after separation was further washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; toluene:ethyl acetate=9:1→7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 2.20 g of the title compound as a white solid. (Yield: 65%)
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:4]=2[O:3]1.[CH:14]1([Mg]Br)[CH2:16][CH2:15]1.ClC1C=C(F)C(C(C2CC2)O)=C(F)C=1>O1CCCC1>[CH:14]1([CH:11]([C:9]2[CH:8]=[CH:7][C:5]3[O:6][C:2]([F:1])([F:13])[O:3][C:4]=3[CH:10]=2)[OH:12])[CH2:16][CH2:15]1
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Agent: OC(c1c(F)cc(Cl)cc1F)C1CC1
Solvent: C1CCOC1
Product: OC(c1ccc2c(c1)OC(F)(F)O2)C1CC1

Procedure:
The title compound was prepared starting from 3.50 g (18.81 mmol) of 2,2-difluoro-5-formylbenzodioxolane and 56.4 ml (28.21 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran in analogy to the synthesis of the compound from Example 156A. 1.59 (37% of theory) of the title compound were obtained.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C[O:13][B:14](OC)[O:15]C>O1CCCC1.CCOCC>[CH2:5]([C:6]1[CH:11]=[CH:10][C:9]([B:14]([OH:15])[OH:13])=[CH:8][CH:7]=1)[CH2:4][CH3:3]
Reactant: COB(OC)OC
Reactant: BrCCCc1ccccc1
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of magnesium shavings (217 mg, 8.9 mmol) in 3 mL of dry tetrahydrofuran under argon, a crystal along with a solution of 4-bromopropylbenzene (1.69 g, 8.5 mmol) dissolved in 6 mL of tetrahydrofuran was added at such a rate that a gentle reflux was maintained. The solution was refluxed for an additional 0.5 h, cooled to room temperature and added in portions over 10 minutes to a solution of trimethylborate (924 mg, 8.9 mmol) previously dissolved in 4 mL of dry ether at -78° C. After 30 minutes, the solution was warmed to room temperature where stirring continued for 90 minutes, then the reaction was quenched by the addition of 2 mL of a 10% hydrochloric acid solution. The tetrahydrofuran was removed under reduced pressure and the remaining residue was extracted into diethyl ether (3×25 mL). The combined ether extracts was extracted with 1M NaOH (3×25 mL) and the resulting aqueous layer was acidified to pH 2.0 using 6N HCl, then reextracted back into diethyl ether (3×25 mL). The combined organic layers was washed with water (1×25 mL), brine (1×25 mL) and dried over magnesium sulfate. Evaporation of solvent left a brown solid which was filtered through a small plug of silica gel using 11.0 MeOH/CACl3. Evaporation left 448 mg (32%) of a brown solid, m.p. 90°-93° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[CH:9]=1.[NH:16]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:25])[C:19]=2[CH:18]=[N:17]1.CCO>C([O-])(O)=O.[Na+]>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[NH:25][C:20]2[C:19]3[CH:18]=[N:17][NH:16][C:24]=3[CH:23]=[CH:22][CH:21]=2)[CH:9]=1
Reactant: Nc1cccc2[nH]ncc12
Reactant: Cc1nc(N)cc(-c2cnccc2Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(N)cc(-c2cnccc2Nc2cccc3[nH]ncc23)n1
Temperature: 160 °C
Yield: 44.1 %

Procedure:
A glass microwave reaction vessel was charged with 6-(4-chloropyridin-3-yl)-2-methylpyrimidin-4-amine (22 mg, 100 μmol), 1H-indazol-4-amine (27 mg, 199 μmol, Bionet) and EtOH (1 mL). The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 160° C. for 30 min. The reaction mixture was diluted with saturated NaHCO3 (2 mL) and extracted with EtOAc (3×20 mL). The organic extract was washed with saturated NaCl (2 mL), dried over Na2SO4, filtered, concentrated and the residue was purified by silica gel chromatography, eluting with 10% MeOH/CH2Cl2/1% NH4OH to give N-(3-(6-amino-2-methylpyrimidin-4-yl)pyridin-4-yl)-1H-indazol-4-amine (14 mg, 44% yield). 1H NMR (300 MHz, CD3OD) δ 8.71 (s, 1H); 8.19 (d, J=6.14 Hz, 1H); 7.34-7.53 (m, 2H); 7.29 (d, J=7.02 Hz, 1H); 7.18 (d, J=6.28 Hz, 1H); 6.90 (s, 1H); 2.59 (s, 3H). m/z (ESI, +ve ion) 318 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.CCN(C(C)C)C(C)C.[F:24][C:25]([F:38])([F:37])[O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.Cl>ClCCl>[CH3:1][C@@H:2]1[N:7]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:37])[F:38])=[CH:32][CH:31]=2)(=[O:35])=[O:34])[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Yield: 90.9 %

Procedure:
To a solution of 1,1-dimethylethyl(3S)-3-methyl-1-piperazinecarboxylate (500 mg, 2.497 mmol) in dichloromethane (20 ml) was added DIPEA (0.654 ml, 3.74 mmol) and then portionwise addition of 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (0.445 ml, 2.62 mmol) at room temperature and the resultant mixture stirred under an atmosphere of argon for 16 hours. The reaction was worked up by the addition of 1M HCl solution (75 mL) and dichloromethane (75 mL), the layers were separated and the organic layer was then washed with 2M NaOH solution (75 mL). The organic phase was separated, dried (MgSO4) and concentrated to dryness to give 1,1-dimethylethyl(3S)-3-methyl-4-({4-[(trifluoromethyl)oxy]phenyl}sulfonyl)-1-piperazinecarboxylate (963 mg, 2.269 mmol). This was dissolved in 1,4-dioxane (4 mL), HCl (4M in 1,4-Dioxane) (2.269 mL, 9.08 mmol) was added and the resultant mixture stirred under an atmosphere of argon for 2 h. After this time a white precipitate had formed so methanol (5 ml) was added to solubilize the precipitate and the reaction stirred for a further 30 min. The reaction was concentrated to dryness giving a white solid which was triturated with Et2O and the solid isolated by filtration under vacuum to give the title compound (585 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5].[Cl:13]S(O)(=O)=O.II.S(Cl)(Cl)=O>O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5].[Cl:1][C:2]1[C:10]([Cl:13])=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5]
Reactant: O=S(=O)(O)Cl
Agent: II
Agent: O=C(Cl)c1cc(F)c(F)cc1Cl
Solvent: O=S(Cl)Cl
Solvent: O
Product: O=C(Cl)c1cc(F)c(F)c(Cl)c1Cl
Temperature: 0 °C
Yield: 71 %

Procedure:
211 g (1 mol) of 2-chloro-4,5-difluorobenzoyl chloride are introduced into 500 g of chlorosulfonic acid, and 3 g of iodine are added. The mixture is chlorinated (10 l/h) for 1.7 h at 40° C. and then diluted with water (500 g), with stirring, the temperature being allowed to rise to 80° C. In this procedure, the acid chlorides initially present in the solvent are hydrolyzed in 2 h to the carboxylic acids, which are isolated by filtration after cooling to 0° C. After drying, the mixture is reacted with thionyl chloride (2 mol) at 80° C. and excess thionyl chloride is then distilled off. The mixture is then distilled, as indicated in Example 1, to give 46.4 g (0.22 mol, 22%) of 2-chloro-4,5-difluorobenzoyl chloride and 174.9 g (0.71 mol, 71%) of 2,3-dichloro-4,5-difluorobenzoyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[N:36]1([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:44]3[CH2:45][CH2:46][CH:41]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:42][CH2:43]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(C)c(-c2nc(N3CCC(N4CCCC4)CC3)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Yield: 54.9 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (17 mg, 0.034 mmol) in DCM (2 mL) was added 4-(1-pyrrolidinyl)piperidine (15 mg, 0.10 mmol). The resultant solution was stirred at room temperature over might. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (11 mg, 55%). LC-MS m/z 592 (M+H)+; 1H-NMR (MeOD) δ 1.00 (t, 3H), 1.34 (m, 2H), 1.68 (m, 3H), 1.90 (m, 5H), 2.31 (s, 3H), 2.36 (m, 1H), 2.68 (m, 6 H), 3.37 (m, 2H), 4.11 (m, 2H), 4.42 (m, 2H), 7.16 (m, 2H), 7.46 (m, 1H), 7.51 (m, 1H), 7.68 (s, 1H), 7.86 (d, 1H).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].Br[C:26]#[N:27]>C(#N)C>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[N:14]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:26]([NH2:27])=[N:24][C:8]=12)[CH2:4][CH3:5])[CH3:2]
Reactant: N#CBr
Reactant: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Solvent: CC#N
Product: CCC(CC)Nc1cc(C)nc2c1nc(N)n2-c1c(C)cc(C)cc1C

Procedure:
The title compound was prepared by reacting N4-(1-ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine with BrCN in acetonitrile at room temperature overnight. The mixture was quenched with water and adjusted to pH 8.0 with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give crude material. The material was purified through silica gel column chromatography to give the title compound as a brown solid, mp. 158-160° C.; Anal. For C21H29N5 ¼H2O calc. C, 70.85; H, 8.35; N, 19.67; found: C, 71.07; H, 8.30; N, 19.63.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@@H:14]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=2[F:44])[C:15]2[S:19][C:18]([NH:20][C:21]([C:23]3([C:26]4[CH:36]=[CH:35][C:29]5[O:30][C:31]([F:34])([F:33])[O:32][C:28]=5[CH:27]=4)[CH2:25][CH2:24]3)=[O:22])=[N:17][CH:16]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O1C2C=CC(C3(C(NC4SC([C@@H](N5CC[C@@H](O[Si](C(C)(C)C)(C)C)C5)C5C=CC(F)=CC=5Cl)=CN=4)=O)CC3)=CC=2OC1.N[C@@H](C1C=CC(Cl)=CC=1F)C1SC(NC(C2(C3C=CC4OC(F)(F)OC=4C=3)CC2)=O)=NC=1.[Si](O[C@@H](CCl)CC=O)(C(C)(C)C)(C)C>CC#N>[Si:1]([O:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=2[F:44])[C:15]2[S:19][C:18]([NH:20][C:21]([C:23]3([C:26]4[CH:36]=[CH:35][C:29]5[O:30][C:31]([F:34])([F:33])[O:32][C:28]=5[CH:27]=4)[CH2:24][CH2:25]3)=[O:22])=[N:17][CH:16]=2)[CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCN([C@H](c2cnc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)s2)c2ccc(Cl)cc2F)C1
Agent: CC(C)(C)[Si](C)(C)O[C@@H](CCl)CC=O
Agent: CC(C)(C)[Si](C)(C)O[C@@H]1CCN([C@H](c2cnc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)s2)c2ccc(F)cc2Cl)C1
Agent: N[C@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)s1)c1ccc(Cl)cc1F
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCN([C@@H](c2cnc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)s2)c2ccc(Cl)cc2F)C1

Procedure:
N-(5-((S)—((R)-3-(tert-Butyldimethylsilyloxy)pyrrolidin-1-yl)(4-chloro-2-fluorophenyl)methyl)thiazol-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide was made by the procedure used for 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((S)—((R)-3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)(2-chloro-4-fluorophenyl)methyl)thiazol-2-yl)cyclopropanecarboxamide, starting from (S)—N-(5-(amino(4-chloro-2-fluorophenyl)methyl)thiazol-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide and (R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanal (90%). 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 7.63 (t, J=8.2 Hz, 1H), 7.43-7.32 (m, 5H), 7.20 (dd, J=1.5, 8.3 Hz, 1H), 4.93 (s, 1H), 4.39-4.34 (m, 1H), 2.69 (dd, J=6.1, 9.8 Hz, 1H), 2.49-2.45 (m, 2H), 2.34 (dd, J=3.9, 9.9 Hz, 1H), 2.10-1.99 (m, 1H), 1.62-1.55 (m, 1H), 1.52-1.49 (m, 2H), 1.24-1.19 (m, 2H), 0.83 (s, 9H), 0.01 (s, 3H), −0.01 (s, 3H); HPLC ret. time 3.79 min, 10-99% CH3CN, 5 min run; ESI-MS 666.3 m/z (MH+).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([N:15]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][C@H:28]([CH2:30]OS(C4C=CC=C([N+]([O-])=O)C=4)(=O)=O)[O:27][C:26]3=[O:44])=[CH:21][C:20]=2[F:45])[CH2:16]1)([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]>CN(C=O)C>[C:5]([N:15]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][C@@H:28]([CH2:30][N:1]=[N+:2]=[N-:3])[O:27][C:26]3=[O:44])=[CH:21][C:20]=2[F:45])[CH2:16]1)([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C(OCc1ccccc1)N1CC(c2ccc(N3C[C@H](COS(=O)(=O)c4cccc([N+](=O)[O-])c4)OC3=O)cc2F)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Reaction time: 16 h

Procedure:
A mixture of sodium azide (1.44 g, 22.1 mmol) and (R)-(−)-N-carbobenzyloxy-3-[2-fluoro-4-[5-[[(3-nitrophenylsulfonyl)oxy]-methyl]-2-3-oxazolidinyl]phenyl]azetidine (Example 81, Step 6, 2.60 g, 4.44 mmol) in DMF (30 mL) was stirred for 16 hr, then filtered. The solvent was removed at 38°/0.75 mm and the residue extracted with ethyl acetate (100 mL) and washed with water (3×50 mL) and brine (50 mL). After drying over magnesium sulfate, filtration and evaporation gave a yellow oil. Chromatography over silica gel (150 g, 40-60 μm) eluting with 1-3% methanol-methylene chloride gave the title compound as a pale yellow foam. FAB-HRMS: theory 426.1577 (M+1); meas. 426.1580.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([SH:16])=[N:12][CH:11]=2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][S:16][C:13]1[CH:14]=[CH:15][C:10]([C:9](=[O:17])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:18]([O-:20])=[O:19])[CH:4]=2)=[CH:11][N:12]=1)[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(S)nc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1ccc(C(=O)Nc2ccc(F)c([N+](=O)[O-])c2)cn1
Reaction time: 0.17 h
Yield: 107.8 %

Procedure:
To mixture of the of N-(4-fluoro-3-nitro-phenyl)-6-mercapto-nicotinamide (200 mg, 0.68 mmol) and ethyl bromoacetate (113 μL, 1.02 mmol) in DMF (5 mL) was added DIPEA (243 μL, 1.4 mmol). The reaction mixture was stirred for 10 minutes before being poured into water and being extracted with ethyl acetate (3×50 mL). The combined extracts were washed with water and brine and were dried over magnesium sulfate. Filtration followed by concentration in vacuo gave 278 mg (100%) of [5-(4-fluoro-3-nitro-phenylcarbamoyl)-pyridin-2-ylsulfanyl]-acetic acid ethyl ester as a solid: 1H NMR (300 MHz, acetone-d6) δ 10.0 (bs, 1H), 9.02 (m, 1H), 8.21 (m, 1H), 8.18 (m, 2H, 7.46 (m, 2H), 4.16 (m, 2H) (s, 2H), 1.22 (m, 3H); MS (EI) m/z 377.88 (M−H)−.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[CH:18]=2)[NH:13][CH:12]=1.B(Br)(Br)Br>ClCCl>[OH:26][C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[C:19]3[C:11]([C:4]4[C:5]([OH:9])=[CH:6][CH:7]=[CH:8][C:3]=4[OH:2])=[CH:12][NH:13][C:14]3=[N:15][CH:16]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(OC)c1-c1c[nH]c2ncc(-c3cccc(O)c3)cc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(-c2cnc3[nH]cc(-c4c(O)cccc4O)c3c2)c1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a suspension of 3-[3-(2,6-dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenol (23 mg, 0.066 mmol) in dichloromethane (1 mL) at −78° C. was added 1 M boron tribromide solution in dichloromethane (0.23 mL, 0.23 mmol) dropwise. The reaction mixture was warmed up to room temperature over 4 h, then quenched with water and neutralized to pH8 with a saturated solution of aqueous sodium bicarbonate. The mixture was extracted with EtOAc three times and the extracts were combined and adsorbed on silica gel. Purification on silica gel with a gradient of methanol/dichloromethane afforded 2-[5-(3-hydroxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]-benzene-1,3-diol as a beige solid (17 mg, 81% yield). 1H NMR (500 MHz, DMSO-d6) δ 6.43 (d, J=8.0 Hz, 1H), 6.73 (dd, J=2.5, 7.5 Hz, 1H), 6.91 (t, J=8.0 Hz, 1H), 7.00 (t, J=2.0 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 7.24 (t, J=8.0 Hz, 1H), 7.46 (d, J=2.5 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 8.42 (d, J=2.0 Hz, 1H), 9.10 (broad s, 2H), 9.49 (broad s, 1H), 11.7 (s, 1H). MS: m/z 319 (M+H+).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:11](=[O:14])[CH2:12][CH3:13])[CH:7]=[CH:8][C:9]=1[Cl:10]>CO>[Br:1][CH:12]([CH3:13])[C:11]([C:6]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=1)=[O:14]
Reactant: CCC(=O)c1ccc(Cl)c(Cl)c1
Reactant: BrBr
Solvent: CO
Product: CC(Br)C(=O)c1ccc(Cl)c(Cl)c1
Yield: 95.9 %

Procedure:
51.1 g (0.320 mol) of bromine was added dropwise to a solution of 65.0 g (0.320 mol) of 3′,4′-dichloropropiophenone in 150 g of methanol at a reaction temperature of 58 to 60° C. After the addition was complete, the methanol was evaporated off from the reaction solution under reduced pressure. The resultant concentrate was dissolved in 130 g of toluene and then washed with water (150 ml×3 times). Thereafter, the toluene was evaporated off under reduced pressure, giving 86.6 g (0.307 mol) of crude brown oily 2-bromo-3′,4′-dichloropropiophenone.
Reaction SMILES: [Br:1][C:2]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:8][C:9]=1[NH:10]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:3]2[C:4]3[C:9](=[CH:8][C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][CH:5]=3)[NH:10][C:11]=2[C:12]([C:16]([OH:18])=[O:17])=[CH:13][C:14]=1[CH3:15]
Reactant: CCOC(=O)C1CCc2c([nH]c3c(C(=O)O)cc(C)c(Br)c23)C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(=O)O)cc(C)c(Br)c12
Reaction time: 0.25 h
Yield: 88.4 %

Procedure:
A solution of 5-bromo-2-(ethoxycarbonyl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid (1.60 g, 4.21 mmol) and 2,3-dichloro-5,6-dicyanobenzoquinone (2.10 g, 9.26 mmol) in THF (45 mL) was heated at 60° C. for 60 min. The cooled mixture was diluted with EtOAc (about 70 mL), stirred for 15 min, and the precipitate was collected by filtration, washed with EtOAc and dried. The filtrate was concentrated, and the residue was triturated with MeOH, filtered, and the collected precipitate was washed with MeOH. The two solids were combined to give 4-bromo-7-(ethoxycarbonyl)-3-methyl-9H-carbazole-1-carboxylic acid as a pale yellow solid (1.40 g, 88% yield). Mass spectrum m/z 376, 378 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][OH:9].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>ClCCl>[C:18]([Si:15]([CH3:17])([CH3:16])[O:9][CH2:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: OCCCc1cccs1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCc1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
To a solution of 3-(thiophene-2-yl)propanol (500 mg, 3.52 mmol) and imidazole (288 mg, 4.22 mmol) in 9 mL anhydrous dichloromethane was added TBS-Cl (584 mg, 3.87 mmol). The resulting mixture was stirred at room temperature for 30 minutes and poured into 50 mL water. Organics were extracted with ether (2×40 mL), dried over magnesium sulfate, filtered and concentrated. The crude oil was subjected to chromatography on silica gel with gradient elution (1-2% ethyl acetate in hexanes) to give tert-butyldimethyl(3-(thiophen-2-yl)propoxy)silane (787 mg, 87%). Used without further characterization.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[Cl:11])=[N+:2]=[N-:3].[C:12]1([CH2:18][C:19]#[CH:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:18]([C:19]1[N:1]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=2[Cl:11])[N:2]=[N:3][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [N-]=[N+]=Nc1cccc(Cl)c1Cl
Reactant: C#CCc1ccccc1
Solvent: Cc1ccccc1
Product: Clc1cccc(-n2nncc2Cc2ccccc2)c1Cl
Temperature: 100 °C

Procedure:
1-Azido-2,3-dichlorobenzene (200 mg, 1.06 mmol) (Cambie J. Organomet. Chem. 1996, 507, 1) and 3-phenyl-1-propyne (150 μL, 1.1 equiv) were combined in toluene (0.2 mL) and heated at 100° C. for 18 hours, allowed to cool to room temperature, and then concentrated under reduced pressure to give a mixture of regioisomers. The residue was purified by flash chromatography eluting with hexanes:ethyl acetate (3:1) to provide the title compound. MS (DCI/NH3) m/z 304 (M+H)+; 1H NMR (CDCl3) δ 3.87 (br s, 2H), 6.98 (m, 2H), 7.13 (dd, 1H), 7.22 (m, 3H), 7.29 (t, 1H), 7.56 (s, 1H), 7.64 (dd, 1H).
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]1[C:18]3[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:17]=3[O:16][N:15]=1)[CH:8]=[CH:7]2.O>C(O)(=O)C>[Br:1][C:5]1[C:4]([OH:3])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([C:14]1[C:18]3[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:17]=3[O:16][N:15]=1)=[CH:10]2
Reactant: BrBr
Reactant: Oc1ccc2cc(-c3noc4cc(O)ccc34)ccc2c1
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc2c(-c3ccc4c(Br)c(O)ccc4c3)noc2c1
Reaction time: 0.5 h
Yield: 53 %

Procedure:
Bromine (0.11 mL, 2.17 mmol) in acetic acid (3 mL) was added dropwise into cold (5° C.) mixture of 3-(6-hydroxy-2-naphthyl)-1,2-benzisoxazol-6-ol (0.6 g, 2.17 mmol) and acetic acid (10 mL). The mixture was stirred for 30 min, poured into water and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/EtOAc 1/1) gave an off-white solid (0.41 g, 53% yield, m.p. 275-277° C.); MS m/e 354 (M−H)+.