Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([O:15][C:16]3[S:17][C:18]4[C:19]([N:24]=3)=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:12]=[CH:11][C:9]=2[CH:10]=1)=O)C.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[S:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[N:24]=[C:16]1[O:15][C:13]1[CH:12]=[CH:11][C:9]2[CH:10]=[C:6]([CH2:4][OH:3])[O:7][C:8]=2[CH:14]=1
Reactant: CCOC(=O)c1cc2ccc(Oc3nc4ncccc4s3)cc2o1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OCc1cc2ccc(Oc3nc4ncccc4s3)cc2o1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
To a cooled (0° C.) solution 6-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-2-carboxylic acid ethyl ester (300 mg, 0.8 mmol) in DCM (8 mL) was added DIBALH (1 M in THF, 3 mL, 3 mmol) and the reaction mixture was warmed (rt, 48 h). The reaction mixture was quenched with saturated aqueous Rochelle's Salt (2 mL) and partitioned with DCM. The organic layer was separated and the aqueous layer was extracted with DCM (2×15 mL). The organic layers were combined, dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using MeOH:DCM (0-10%) to provide the title compound as a yellow solid (197 mg, 82%). MS (ESI): mass calcd. for C16H10N2O3S, 298.1; m/z found, 299.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 8.53 (dd, J=4.8, 1.7, 1H), 8.40 (dd, J=8.0, 1.7, 1H), 7.84 (d, J=1.7, 1H), 7.74 (d, J=8.4, 1H), 7.44-7.26 (m, 2H), 6.86 (s, 1H), 5.54 (t, J=5.9, 1H), 4.60 (d, J=5.9, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].[CH3:12][O:13][C:14](=[O:17])[CH2:15][NH2:16]>>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:16][CH2:15][C:14]([O:13][CH3:12])=[O:17])=[O:9])=[CH:10][CH:11]=1)=[O:2]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: COC(=O)CN
Product: COC(=O)CNC(=O)c1ccc(C=O)cc1
Yield: 81.5 %

Procedure:
In an analogous manner to 35, 4-formyl benzoic acid 24 (1.0 g, 6.66 mmol) was reacted with glycine methyl ester (653 mg, 7.33 mmol) to give 1.2 gm (81%) of methyl 2-(4-formylbenzamido)acetate 37 as an off-white solid (81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[NH:5][C:6]1[C:14]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[N+:19]([O-])=O.N(C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[NH2:19][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([S:15](=[O:18])(=[O:17])[NH2:16])[C:6]=1[NH:5][C:4]1[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=1[O:2][CH3:1])[C:10]([OH:12])=[O:11]
Reactant: COc1ccccc1Nc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Product: COc1ccccc1Nc1c(N)cc(C(=O)O)cc1S(N)(=O)=O

Procedure:
By substituting 4-(o-methoxyanilino)-3-nitro-5-sulphamyl-benzoic acid for the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the above compound was obtained after recrystallization from aqueous ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([NH:29][C:30]4[CH:31]=[N:32][CH:33]=[N:34][CH:35]=4)=[C:22]([CH:28]=3)[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([NH:29][C:30]4[CH:31]=[N:32][CH:33]=[N:34][CH:35]=4)=[C:22]([CH:28]=3)[C:23]([N:25]([CH3:26])[CH3:27])=[O:24])[CH:16]=2)[NH:11][CH:10]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(Nc4cncnc4)c(C(=O)N(C)C)c3)cc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(Nc4cncnc4)c(C(=O)N(C)C)c3)cc12
Reaction time: 4.5 h
Yield: 42.7 %

Procedure:
67 mg (0.11 mmol) of 5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-2-(pyrimidin-5-ylamino)-benzamide was dissolved in 3 mL of hot ethanol. 200 μL of 50% w/v aqueous potassium hydroxide was added and the mixture left at ambient temperature for 4.5 h. 10% w/v aqueous citric acid was added and the mixture partitioned between dichloromethane and water. The aqueous layer was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated. The residue was purified by mass-triggered reverse-phase HPLC to afford 21.9 mg (47 μmol, 43%) of 5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-2-(pyrimidin-5-ylamino)-benzamide as a beige solid. 1H-NMR (500 MHz, d6-DMSO): δ 11.91 (s, br., 1H), 8.64 (s, 1H), 8.55 (d, 1H), 8.51 (s, 2H), 8.17 (d, 1H), 8.12 (s, 1H), 7.74 (d, 1H), 7.73 (dd, 1H), 7.63-7.61 (m, 2H), 7.39 (d, 1H), 7.30 (dd(d), 1H), 7.14 (d, 1H), 7.06 (t, 1H), 3.83 (s, 3H), 2.90 (s, 3H), 2.88 (s, 3H); MS: m/z 465.0 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:29])=[C:9]([C:25]([O:27][CH3:28])=[O:26])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[Cl:24])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].S(O)(O)(=O)=O.CS[C:37](=[NH:39])[NH2:38].C(N(CC)CC)C>C(O)CC>[Cl:24][C:18]1[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:25]([O:27][CH3:28])=[O:26])=[C:8]([CH3:29])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][C:37]([NH2:39])=[NH:38])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CSC(=N)N
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CCCO
Product: CCOC(=O)C1=C(COCCNC(=N)N)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 74.9 %

Procedure:
2-(2-Aminoethoxymethyl)-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (5.0 g) and S-methylisothiourea sulphate (3.45 g) was suspended in n-propanol (120 ml) and triethylamine (30 ml) and refluxed for 17 hours. After evaporation to dryness, the residual oil was partitioned between aqueous sodium bicarbonate and methylene chloride. The organic layer was dried (MgSO4), filtered and evaporated. The resultant beige solid was triturated with hexane to give the title compound (4.1 g), N.M.R. (CDCl3, 60 MHz): 3H 1.15(t), 3H 3.55(s), 4H 3.7(m), 2H 4.0(q), 2H 4.7(s), 1H 5.45(s), 8H 7.25(m).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@:3]1([CH2:11][CH3:12])[C:7]([O:9][CH3:10])=[O:8].Cl.[CH3:14][C:15]1[CH:24]=[C:23]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>>[CH2:11]([C@:3]1([C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:5][CH2:6][C@H:2]1[NH:1][S:33]([C:30]1[CH:31]=[CH:32][C:27]([O:26][CH2:25][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([CH3:14])[CH:24]=2)=[CH:28][CH:29]=1)(=[O:34])=[O:35])[CH3:12]
Reactant: CC[C@]1(C(=O)OC)CCC[C@H]1N
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Product: CC[C@]1(C(=O)OC)CCC[C@H]1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Yield: 64 %

Procedure:
According to the procedure of Example 53, Step 3, using methyl (1S,2R)-2-amino-1-ethylcyclopentanecarboxylate (410 mg, 1.97 mmol) and 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride (917 mg, 2.39 mmol), methyl (1S,2R)-1-ethyl-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylate (609 mg, 1.26 mmol, 64%) was obtained as a colorless solid after purification via column chromatography on silica gel, eluting with 30% ethyl acetate/hexanes. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.80-0.86 (m, 3H) 1.37-1.41 (m, 1H) 1.42-1.48 (m, 2H) 1.50-1.55 (m, 1H) 1.58-1.65 (m, 2H) 1.71-1.82 (m, 2H) 2.12 (ddd, J=12.76, 8.72, 3.54 Hz, 1H) 2.75-2.77 (m, 3H) 3.42 (td, J=9.79, 7.71 Hz, 1H) 3.69-3.71 (m, 3H) 5.57 (s, 2H) 5.64 (d, J=9.60 Hz, 1H) 7.09-7.13 (m, 2H) 7.43 (s, 1H) 7.56 (ddd, J=8.34, 7.07, 1.26 Hz, 1H) 7.74 (ddd, J=8.40, 7.01, 1.52 Hz, 1H) 7.83-7.92 (m, 3H) 8.10 (d, J=7.83 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[N:19][CH:20]=1>>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=3)[CH:7]=2)[CH:18]=[N:19][CH:20]=1
Reactant: O=Cc1cnc2ccc(Br)cn12
Reactant: OB(O)c1cncc(C(F)(F)F)c1
Product: O=Cc1cnc2ccc(-c3cncc(C(F)(F)F)c3)cn12
Yield: 48 %

Procedure:
The title compound was prepared by following the procedure as described for Intermediate 1 using 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde and 5-(trifluoromethyl)pyridin-3-ylboronic acid. Yield: 48%; 1H NMR (DMSO-d6; 300 MHz): δ 10.04 (s, 1H), 9.71 (s, 1H), 9.27 (s, 1H), 9.07 (s, 1H), 8.62 (s, 2H), 8.16-8.19 (dd, 1H, J=1.8&9.3 Hz), 8.03-8.04 (d, 1H, J=9.3 Hz); MS: m/z 292 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][CH:13]=O.Cl.[C:16]([O:20][NH2:21])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][N:21]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=[CH:13]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: O=CNc1cnc2ccccc2c1Cl
Reactant: CC(C)(C)ON
Agent: Cl
Product: CC(C)(C)On1cnc2cnc3ccccc3c21
Yield: 70.5 %

Procedure:
4-Chloroquinolin-3-ylformamide (4.1 g, 0.020 mol) was treated with O-(tert-butyl)hydroxylamine hydrochloride (2.8 g, 22 mmol) according to the method of Part B of Example 20 to provide 3.4 g of 1-tert-butoxy-1H-imidazo[4,5-c]quinoline, which was used without chromatographic purification.
Reaction SMILES: [F:1]F.[F:3][C:4]1[N:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[N:5]=1.[F-].[Na+]>ClC(Cl)(Cl)F>[F:10][C:8]1[N:9]=[C:4]([F:3])[N:5]=[C:6]([F:11])[C:7]=1[F:1]
Reactant: Fc1cc(F)nc(F)n1
Reactant: FF
Agent: [F-]
Agent: [Na+]
Solvent: FC(Cl)(Cl)Cl
Product: Fc1nc(F)c(F)c(F)n1
Yield: 63.9 %

Procedure:
0.5 mol of fluorine in the form of a 30% by volume mixture with helium was introduced into a suspension of 29.0 g (0.216 mol) of 2,4,6-trifluoropyrimidine, 21 g of sodium fluoride (0.5 mol) and 250 ml of trichlorofluoromethane at a temperature of -78° C. The rate of introduction was 0.15 mol of fluorine per hour. After the introduction was complete, the reaction mixture was filtered and 21.0 g of tetrafluoropyrimidine (=64% of theory) were obtained from the filtrate by distillation.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([Cl:18])=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:21][C:22]1[S:26][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH3:37].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CC(C)=O>[C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:21][C:22]3[S:26][C:25]([C:27]4[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=4)=[N:24][C:23]=3[CH3:37])[CH:15]=2)[C:10]([Cl:18])=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: CC(C)(C)OC(=O)Cn1cc(Cl)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2c(Cl)cn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 1 a], (3-chloro-6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester was reacted with 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole [PCT Int. Appl. (2002), WO 0292590 A1] in the presence of cesium carbonate and potassium iodide in acetone for 14 h at ambient temperature to give the title compound as yellow crystals.
Reaction SMILES: COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:10]2)=CC=1.[C:23]([C:25]1[C:30]2[N:31]=[C:32]([CH:34]3[CH2:36][CH2:35]3)[O:33][C:29]=2[C:28]([CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=O)=[C:27]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:26]=1[CH3:49])#[N:24]>C1(C)C=CC=CC=1>[C:23]([C:25]1[C:30]2[N:31]=[C:32]([CH:34]3[CH2:36][CH2:35]3)[O:33][C:29]=2[C:28]([CH2:37][C:38](=[S:10])[N:40]([CH3:42])[CH3:41])=[C:27]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:26]=1[CH3:49])#[N:24]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1c(-c2ccccc2)c(CC(=O)N(C)C)c2oc(C3CC3)nc2c1C#N
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2)c(CC(=S)N(C)C)c2oc(C3CC3)nc2c1C#N
Temperature: 125 °C
Reaction time: 5 h
Yield: 66.6 %

Procedure:
2,4-Bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4-disulfide (24.8 mg, 0.061 mmol) was added to a toluene (1 ml) solution of 2-(4-cyano-2-cyclopropyl-5-methyl-6-phenyl-1,3-benzoxazol-7-yl)-N,N-dimethylacetamide (I-313) (20.0 mg, 0.056 mmol), followed by stirring in ah oil bath at 125° C. for 5 hours. The reaction liquid was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:1, v/v) to obtain the entitled compound (14.0 mg, 67%) as a yellow solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([O:20]C(=O)C(C)(C)C)[CH:14]=[CH:13][C:12]=2[CH2:11]1)[CH3:2].C(OC(=O)[NH:33][C:34]([CH3:46])([CH3:45])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]=O)=[CH:39][CH:38]=1)(C)(C)C>>[NH2:33][C:34]([CH3:45])([CH3:46])[CH2:35][O:36][C:37]1[CH:38]=[CH:39][C:40]([CH2:43][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C@H:10]2[CH2:19][CH2:18][C:17]3[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=3[CH2:11]2)=[CH:41][CH:42]=1
Reactant: CCNc1ccccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(COc1ccc(C=O)cc1)NC(=O)OC(C)(C)C
Product: CC(C)(N)COc1ccc(CCCNc2ccccc2[C@H]2CCc3cc(O)ccc3C2)cc1
Yield: 52.7 %

Procedure:
Synthesized from pivalic acid (S)-6-(2-ethylaminophenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and tert-butyl[2-(4-formylphenoxy)-1,1-dimethylethyl]carbamate (125 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (20 mg) was obtained.
Reaction SMILES: [Mg].II.[F:4][C:5]1[CH:6]=[C:7](Br)[CH:8]=[CH:9][CH:10]=1.C([O:14][CH2:15][CH3:16])=O.[Cl-].[NH4+]>C1COCC1.O>[F:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH:15]([OH:14])[C:16]1[CH:8]=[CH:9][CH:10]=[C:5]([F:4])[CH:6]=1
Reactant: CCOC=O
Reactant: Fc1cccc(Br)c1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: OC(c1cccc(F)c1)c1cccc(F)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
To a stirred solution of magnesium strip (35.4 g) in THF (200 ml), iodine strip was added and the mixture was heated with stirring under nitrogen stream until most of color of iodine was disappeared. A solution of 3-fluoro-bromobenzene (250.0 g) in THF (1000 ml) was added dropwise over 2.5 hr while the temperature of the solution was maintained at 60° C., After the completion of the addition of the solution, the resulting mixture was refluxed for 1 hr with heating. The resulting Grignard solution was ice-cooled and a solution of ethyl formate (63.2 g) in THF (200 ml) was added dropwise over 1 hr. After a stirring of the reaction solution for an additional 30 min, saturated aqueous ammonium chloride solution (700 ml) was added dropwise with ice-cooling and water (300 ml) was added. The mixture was stirred for 10 min. The organic layer and water layer were separated. Water layer was extracted with ethyl acetate, and the combined organic layer was washed with 2N hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated off under reduced pressure to give the title compound (156.2 g, yield 99%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5](I)=[CH:4][N:3]=1.[C:14]([C:16]1[CH:17]=[N:18][N:19]([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:20]=1)#[CH:15].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[Br:1][C:2]1[N:3]=[CH:4][C:5]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:20]=3)[N:8]([S:9]([CH3:12])(=[O:11])=[O:10])[C:6]=2[CH:7]=1
Reactant: CS(=O)(=O)Nc1cc(Br)ncc1I
Reactant: C#Cc1cnn(CC(=O)N(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cn1cc(-c2cc3cnc(Br)cc3n2S(C)(=O)=O)cn1
Temperature: 60 °C
Yield: 41.4 %

Procedure:
Bis(triphenylphosphine)palladiumdichloride (69 mg, 0.099 mmol) was added to a solution of N-(2-bromo-5-iodopyridin-4-yl)methanesulfonamide (Preparation 8, 0.5 g, 1.98 mmol), 2-(4-ethynyl-1H-pyrazol-1-yl)-N,N-dimethylacetamide (Preparation 101, 0.3 g, 1.7 mmol), triethylamine (1.05 g, 1.05 mmol) and copper iodide (19.5 mg, 0.098 mmol) in DMF (5 ml). The reaction mixture was heated for 1 hour at 60° C. The reaction was cooled to room temperature and diluted with ethyl acetate. The organic solution was washed with water, brine and dried over sodium sulphate. The solvent was removed in vacuum and the crude product purified on silica gel column chromatography eluting with a gradient of 10 to 20% methanol in ethyl acetate to afford the title compound as a white powder (0.3 g, 88%). 1H-NMR (500 MHz, d6-DMSO): δ 2.86 (s, 3H), 3.04 (s, 1H), 3.42 (s, 3H), 5.2 (s, 2H), 6.96 (s, 1H), 7.76 (s, 1H), 8.05 (s, 2H), 8.72 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=4)[CH:20]=[C:19]([C:32](OC)=[O:33])[N:18]=3)[N:12]=2)[CH:8]=[C:7]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([N+:42]([O-:44])=[O:43])[CH:37]=2)[CH:6]=1)=O.OCC1N=C(C2C=CC=C(C3C=C(C4C=CC=CC=4)C=C(CO)N=3)N=2)C=C(C2C=CC=CC=2)C=1>>[OH:2][CH2:3][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=4)[CH:20]=[C:19]([CH2:32][OH:33])[N:18]=3)[N:12]=2)[CH:8]=[C:7]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([N+:42]([O-:44])=[O:43])[CH:37]=2)[CH:6]=1
Reactant: COC(=O)c1cc(-c2cccc([N+](=O)[O-])c2)cc(-c2cccc(-c3cc(-c4cccc([N+](=O)[O-])c4)cc(C(=O)OC)n3)n2)n1
Agent: OCc1cc(-c2ccccc2)cc(-c2cccc(-c3cc(-c4ccccc4)cc(CO)n3)n2)n1
Product: O=[N+]([O-])c1cccc(-c2cc(CO)nc(-c3cccc(-c4cc(-c5cccc([N+](=O)[O-])c5)cc(CO)n4)n3)c2)c1
Yield: 56 %

Procedure:
Compound 18c was synthesized from 17c using a method analogous to the synthesis described in 18a.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:20])([F:19])[O:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1.CC(CCC)C(=O)C(=O)C(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.Cl[Cu].CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:9])([F:19])[F:20])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: Sc1ccc(Br)cc1
Agent: Cl[Cu]
Agent: CCCC(C)C(=O)C(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(Sc2ccc(Br)cc2)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
N-Methyl-2-pyrrolidone (10 mL) was added to 4-bromothiophenol (0.500 g, 2.64 mmol) in a sealed tube and the mixture was purged with argon for 5 minutes. After this time, 4-trifluoromethoxy-iodobenzene (0.73 g, 2.53 mmol), CuCl (0.131 g, 1.32 mmol), tetramethyl heptanedione (0.14 mL, 0.66 mmol) and cesium carbonate (1.70 g, 5.28 mmol) were added to the reaction mixture. The reaction mixture was stirred at 130° C. under argon for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a celite bed. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the crude product. Silica gel chromatography (neat hexanes) provided impure 1-bromo-4-(4-(trifluoromethoxy)phenyl-sulfanyl)benzene (0.62 g) as a liquid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Br:7].C([Li])CCC.[Br-].[Mg+2].[Br-].[C:16]([O:20]OC(=O)C1C=CC=CC=1)([CH3:19])([CH3:18])[CH3:17]>C(OCC)C>[Br:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[O:20][C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: Brc1ccsc1Br
Reactant: CC(C)(C)OOC(=O)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(C)(C)Oc1sccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A -78° C. solution of 2,3-dibromothiophene (Aldrich, 10.0 g, 41.3 mmol) in 150 mL of diethyl ether was treated with n-butyl lithium (2.5 M, 16.5 mL) over a 20 min period. The mixture was stirred 1h at -78° C. Magnesium bromide (13.0 g, 49.6 mmol) was added as a solid in two portions. The mixture was stirred at -780° C. for 1h and rt for 2h. t-Butylperbenzoate was added at 0° C. and the reaction was allowed to stir at ambient temperature overnight. The mixture was quenched with ice water (50 mL) and 2N HCl (25 mi). The organic layer was separated and washed once with ice cold 1 N NAOH, water and brine. The organic layer was dried over magnesium sulfate and concentrated to give 10.5 g (98%) of the title compound: MS: m/z 236 MH+); 1H NMR(CDCl3): d 1.36 (s, 9H), 6.61 (d, j=6.1 Hz, 1H) and 7.23 (d, J=6.1 Hz, 1H).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][C:7]=1[O:15]C>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][C:7]=1[OH:15]
Reactant: COc1cc(CC#N)ccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#CCc1ccc(Cl)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
BBr3 (16.6 g, 66 mmol) was slowly added to a solution of 2-(4-chloro-3-methoxyphenyl)acetonitrile (12 g, 66 mmol) in DCM (120 mL) at −78° C. under N2. The reaction temperature was slowly increased to room temperature. The reaction mixture was stirred overnight and then poured into ice-water. The organic layer was separated and the aqueous layer was extracted with DCM (40 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated under vacuum to give (4-chloro-3-hydroxy-phenyl)-acetonitrile (9.3 g, 85%). 1H NMR (300 MHz, CDCl3) δ 7.34 (d, J=8.4 Hz, 1 H), 7.02 (d, J=2.1 Hz, 1 H), 6.87 (dd, J=2.1, 8.4 Hz, 1 H), 5.15 (brs, 1 H), 3.72 (s, 2 H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:11][CH2:10][CH2:9][C:8]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][C:6]=2[CH:21]=1.[CH2:22]([O:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1)[CH2:23][CH2:24]C.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C(CCO)=CC=CC=1.O.[Pd].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.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>[CH2:13]([N:12]1[C:5]2[CH:4]=[CH:3][C:2]([C:33]3[CH:34]=[CH:35][C:30]([O:29][CH2:28][CH2:27][O:26][CH2:22][CH2:23][CH3:24])=[CH:31][CH:32]=3)=[CH:21][C:6]=2[CH:7]=[C:8]([C:17]([O:19][CH3:20])=[O:18])[CH2:9][CH2:10][CH2:11]1)[CH:14]([CH3:16])[CH3:15]
Reactant: CCCCOCCOc1ccc(OB(O)O)cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(CC(C)C)CCC1
Agent: [Pd]
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Solvent: O
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
Under argon atmosphere, a mixture of methyl 8-bromo-1-isobutyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylate (1.3 g), 4-(2-butoxyethoxy)phenyl boric acid (1.07 g) and potassium carbonate (1.02 g) in toluene-ethanol-water (40-4-4 ml) was stirred at room temperature for 1 hour. To the reaction system was added tetrakis(triphenylphosphine)-palladium (0.21 g), and the mixture was refluxed for 5 hours. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. After concentration under reduced pressure, the residue was separated to purify by column chromatography (ethyl acetate:hexane=1:49→1:19→1:9) to give methyl 1-isobutyl-8-[4-(2-propoxyethoxy)phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylate (1.20 g) as a yellow oily material.