Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[OH:33])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=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)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:41]1[CH2:45][CH2:44][NH:43][C:42]1=[O:46].O>CS(C)=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH:41]2[CH2:45][CH2:44][NH:43][C:42]2=[O:46])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([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:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NCCC1Br
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)/C(=N\OC1CCNC1=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.7 %

Procedure:
15.8 g of ethyl (Z)-2-(2-tritylaminothiazol-4-yl)-2-hydroxyiminoacetate are dissolved in 70 ml of dimethylsulfoxide, and 5.8 g of anhydrous potassium carbonate are added thereto. The mixture is stirred at room temperature for 20 minutes. 6.6 g of 3-bromo-2-pyrrolidone are added to said mixture, and the mixture is stirred at room temperature for 20 hours. The mixture is poured into 800 ml of water, and crystalline precipitates are collected by filtration and washed with water. The crystals are dissolved in chloroform, washed with water and then dried. Then, the chloroform solution is evaporated under reduced pressure to remove solvent. 100 ml of ethyl acetate are added to the residue, and allowed to stand at room temperature. Crystalline precipitates thus obtained are collected by filtration and dried. 16.0 g of ethyl (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(2-pyrrolidon-3-yl)oxyimino]acetate are obtained.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][C:9](CCCC(O)=O)=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].CCN=C=NCCCN(C)C.Cl.C(O)C(N)(CO)CO>C1N(CCS(O)(=O)=O)CCOC1>[N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2]
Reactant: Cn1c(=O)c2[nH]c(CCCC(=O)O)nc2n(C)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC(CO)(CO)CO
Product: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2 mg of theophylline-8-butanoic acid (Sigma) was dissolved in 4 ml of 0.1 M MES buffer solution. Thereafter, 7 mg of WSC hydrochloride and 5 mg of NHS were added thereto, and the mixture was stirred at room temperature for 15 minutes. Thereafter, 10 mg of BSA (Sigma) was dissolved in 2 ml of 0.1 M MES, and the obtained solution was added to the above reaction product. The obtained mixture was reacted at room temperature for 2 hours. 500 μl of a 1M Tris buffer solution (pH 7.5) was added to the mixture, and the reaction was terminated. Thereafter, dialysis was carried out against 0.1 M Tris buffer solution (pH 7.5).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[OH:8].[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21](Br)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>>[F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)=[CH:23][N:22]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: OB(O)c1ccc(O)c(F)c1
Product: Oc1ccc(-c2ccc(Cn3ccnc3)cn2)cc1F

Procedure:
Synthesized using 3-fluoro-4-hydroxyphenylboronic acid (196 mg, 2.00 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 40 mg, 0.15 mmol, 24%. 1H NMR (500 MHz, DMSO-d6): δH (ppm): 5.25 (s, 2H), 6.92 (brs, 1H), 7.03 (t, J=8.8 Hz, 1H), 7.25 (t, J=1.2 Hz, 1H), 7.69 (dd, J=8.2, 2.2 Hz, 1H), 7.74 (ddd, J=8.5, 2.2, 0.6 Hz, 1H), 7.80 (brs, 1H), 7.83 (dd, J=13.0 Hz, 2.2 Hz, 1H), 7.87 (dd, J=8.2, 0.6 Hz, 1H), 8.57 (dd, J=2.2, 0.6 Hz, 1H), 10.2 (s, 1H); MS (ESI): m/z=270.12 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH:14]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](I)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:13]=1)=[O:8].[F:32][C:33]([F:45])([F:44])[O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH:14]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25]([C:38]3[CH:37]=[CH:36][C:35]([O:34][C:33]([F:32])([F:44])[F:45])=[CH:40][CH:39]=3)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:13]=1)=[O:8]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Oc2cc(C)c(I)c(C)c2)s1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: COC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Oc2cc(C)c(-c3ccc(OC(F)(F)F)cc3)c(C)c2)s1

Procedure:
This compound is made by the general method as exemplified in Preparation 77 using 3-({5-[4,4,4-trifluoro-1-(4-iodo-3,5-dimethyl-phenoxy)-butyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester - chiral Isomer 1 and 4-trifluoromethoxy-phenyl boronic acid as the starting materials. MS(ES): 604.3 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:28]([O-:30])=[O:29])=[C:7]([NH:9][C:10]2[S:11][C:12]([C:25]([NH2:27])=[O:26])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([F:24])([F:23])[F:22])[N:14]=2)[CH:8]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>ClCCl>[CH3:45][N:46]1[CH2:51][CH2:50][N:49]([CH2:1][C:3]2[CH:4]=[CH:5][C:6]([N+:28]([O-:30])=[O:29])=[C:7]([NH:9][C:10]3[S:11][C:12]([C:25]([NH2:27])=[O:26])=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:21]([F:23])([F:22])[F:24])[N:14]=3)[CH:8]=2)[CH2:48][CH2:47]1
Reactant: NC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1ccccc1C(F)(F)F
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc([N+](=O)[O-])c(Nc3nc(-c4ccccc4C(F)(F)F)c(C(N)=O)s3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution 0.18 g (0.41 mmole) of 2-(5-formyl-2-nitro-phenylamino)-4-(2-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (VI.17b) and 0.18 g (0.83 mmole) of sodium triacetoxy-borohydride in 15 mL of dichloromethane was added 0.069 mL (0.62 mmole) of 1-methylpiperazine. The mixture was stirred at room temperature overnight. The mixture was then diluted with dichloromethane, washed with saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification of the residue by silica gel chromatography, eluting with dichloromethane-methanol (gradient 100:0-75:25) gave 0.16 g of 2-[5-(4-methyl-piperazin-1-ylmethyl)-2-nitro-phenylamino]-4-(2-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (VI.17c) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:35])[C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3](OCC)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH3:8][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:35])[C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:1])[CH2:3][OH:4]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(=O)c3cc(Cl)ccc3OC)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(-c2ccc(OC(C)(C)CO)cc2)cc1

Procedure:
3.5 gm (7 millimols) of ethyl 2-methyl-2-{4-[2-(2-methoxy-5-chloro-benzamido)-ethyl]-biphenyl-4'-oxy}-propionate were reduced in 30 ml of absolute ether with 0.27 gm (7 millimols) of lithium aluminum hydride. After careful addition of 8 ml of water, the mixture was filtered, the filter cake was washed first with ether and then with chloroform, the ether phase and the chloroform phase were combined with the filrate and dried over sodium sulfate. After distilling off the solvents, the residual oil was crystallized from a small quantity of ether. Yield: 1.2 gm (38% of theory); m.p. 115° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[I:9].Cl.[C:11]1(Cl)[C:17](=O)C(Cl)=C(Cl)[C:13](=O)[C:12]=1Cl.C(=O)/C=C/C>C(O)(C)C.CCOC(C)=O.[NH4+].[OH-]>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[I:9])[N:8]=[C:12]([CH3:13])[CH:11]=[CH:17]2
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: Nc1ccc(Br)c(I)c1
Agent: C/C=C/C=O
Agent: Cl
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1ccc2cc(Br)c(I)cc2n1
Temperature: 25 °C

Procedure:
To (4-bromo-3-iodophenyl)amine (11.93 g, 40 mmol) was added conc HCl (6 ml), p-chloranil (9.83 g, 1 equiv.) and isopropanol (20 ml) and the mixture was heated to reflux. A solution of crotonaldehyde (3.98 ml) in isopropanol (3.8 ml) was then added at a rate of 0.1 ml/min using a syringe pump and the mixture was stirred at reflux for another 40 min after the end of the addition. The mixture was cooled to r.t., diluted with EtOAc and 5% aq. NH4OH. The products were extracted in EtOAc and the organic layer was washed several times with water, brine, and dried over Na2SO4. The crude material was dissolved as much as possible in 300 ml boiling toluene and purified by flash chromatography on silica with a gradient of EtOAc/toluene 0 to 5%. The first product was 6-bromo-7-iodo-2-methylquinoline followed by its isomer 6-bromo-5-iodo-2-methylquinoline.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][N+:4]=1[O-])[CH3:2].[C:12]([O:15]C(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:15][CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][N:4]=1)[CH3:2])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cc(OC)cc[n+]1[O-]
Product: COc1ccnc(C(C)OC(C)=O)c1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 78 %

Procedure:
171 g of 2-ethyl-4-methoxy-pyridine N-oxide are added dropwise within 3 h to 312 ml of acetic anhydride heated to 90° C., in such a way that the internal temperature does not exceed 115° C. The mixture is then left to stand for a further 2.5 h at 100° C., and excess acetic anhydride is stripped off. Distillation of the residue gives 171 g (78%) of the title compound of b.p. 100° C./1 Pa.
Reaction SMILES: C(N)CCC.NO.Cl.[CH:9]#[C:10][CH2:11][C@@H:12]([OH:22])[C@H:13]([OH:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Br[C:24]#[C:25][C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[OH:27]>C(Cl)Cl.[Cu]Cl>[C:28]1([C@@H:26]([OH:27])[C:25]#[C:24][C:9]#[C:10][CH2:11][C@@H:12]([OH:22])[C@H:13]([OH:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C#CC[C@@H](O)[C@H](O)CCCCCCC
Reactant: O[C@@H](C#CBr)c1ccccc1
Agent: Cl[Cu]
Agent: Cl
Agent: NO
Solvent: ClCCl
Solvent: CCCCN
Product: CCCCCCC[C@@H](O)[C@H](O)CC#CC#C[C@H](O)c1ccccc1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
Copper(I) chloride (6.4 mg, 64.6 μmol, 20 mol %) was added to a stirred solution of n-BuNH2 (0.32 mL) and distilled water (0.74 mL) at 0° C., which resulted in a deep blue solution. A few crystals of NH2OH.HCl were added to get a colorless solution which is indicative of the presence of the required Cu(I) salt. At the same temperature was added (4R,5R)-1-dodecyne-4,5-diol (64.1 mg, 0.323 mmol) by cannula as a solution in CH2Cl2 (0.6 mL). Then a freshly prepared solution of (R)-3-bromo-1-phenyl-2-propyn-1-ol (75.0 mg, 0.355 mmol, 1.1 equiv) in CH2Cl2 (2.4 mL) was slowly added over 60 min by help of syringe pump under a flow of argon in order to prevent the solution from turning to green or blue (NH2OH.HCl can be added as necessary throughout the reaction). The reaction mixture was allowed to warm up to room temperature. After stiffing for 10˜20 minutes, the brownish orange colored solution was extracted three times with CH2Cl2, washed with brine, dried over Na2SO4, filtered and concentrated. The reaction procedure in Cho, E. J.; Kim, M.; Lee, D. Org. Lett. 2006, 8, 5413-54169 and supporting information, both of which are incorporated herein by reference in their entireties, can also be followed. Purification of the crude mixture by gradient flash chromatography on silica gel (hexanes/EtOAc=2.5:1→2:1→1.5:1→1:1) afforded the title compound (83.2 mg, 78%) as a white solid: 1H-NMR (CDCl3, 500 MHz) δ 7.51-7.38 (m, 2H), 7.40-7.32 (m, 3H), 5.50 (s, 1H), 3.63-3.60 (m, 2H), 2.62-2.53 (m, 3H), 2.17 (br s, 1H), 1.68 (br s, 1H), 1.50-1.28 (m, 12H), 0.88 (t, J=7.0 Hz, 3H); 13C-NMR (CDCl3, 75 MHz) δ 139.68, 128.71, 128.62, 126.60, 78.40, 75.64, 73.07, 72.11, 71.23, 66.52, 64.86, 33.49, 31.78, 29.52, 29.20, 25.55, 24.92, 22.62, 14.09.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:22]([C:25]1[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=1)=[C:23]=[O:24].CCN(C(C)C)C(C)C>O1CCOCC1>[CH:31]([C:28]1[CH:29]=[CH:30][C:25]([NH:22][C:23]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:16]=[CH:15][N:14]=[C:13]4[C:8]=3[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[C:11](=[O:17])[NH:12]4)[CH2:6][CH2:5]2)=[O:24])=[CH:26][CH:27]=1)([CH3:33])[CH3:32]
Reactant: O=c1[nH]c2nccc(N3CCNCC3)c2c2ccccc12
Reactant: CC(C)c1ccc(N=C=O)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccc(NC(=O)N2CCN(c3ccnc4[nH]c(=O)c5ccccc5c34)CC2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
Compound 179 (50 mg, 0.14 mmol), 1-isocyanato-4-isopropyl-benzene (34 mg, 0.21 mmol), and DIEA (0.07 mL, 0.42 mmol) were suspended in dioxane (2 mL), and stirred overnight at 80° C. The reaction mixture was quenched with 1M HCl, and diluted with EtOAc. The mixture was filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 75 to 100 EtOAc in hexane to provide 197 (40 mg, 64% yield) as a yellow solid. LC-MS (M+H=442, obsd.=442).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=2)=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl.C(OCC)(=O)C>[Si:26]([O:1][CH2:2][C:3]1[S:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=2)=[CH:6][CH:7]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc(-c2cccc(Br)c2)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(-c2cccc(Br)c2)s1
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(hydroxymethyl)-5-(3'-bromophenyl)thiophene (1.08 G; 4 mM) and triethylamine (1.4 mL; 10 mM) in 20 ml of methylene chloride at R.T. was added t-butyldimethylchlorosilane (1.5 g; 10 mM). This mixture was stirred overnight, diluted with 30 ml of ethyl acetate, washed with 2×15 ml of sat'd. sodium chloride solution, and dried over anhyd. magnesium sulfate. Solvent was removed to give a residue, which was purified on silica gel with ether:petroleum ether (1:20) as solvent mixture. Eluate was distilled to give 0.99 g of 2-(t-butyldimethylsilyloxymethyl)-5-(3'bromophenyl)thiophene as colorless liquid boiling at 167°-170°/~0.2 mm.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[CH:3]([CH:28](C(OCC)=O)[C:29]([O:31]CC)=[O:30])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[CH:18]=[C:19]([C:21]4[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=4)[S:20][C:13]=23)=[C:7]([F:27])[CH:6]=1.[OH-].[Na+]>O.C(O)C>[F:40][C:2]([F:1])([F:39])[CH:3]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[CH:18]=[C:19]([C:21]4[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=4)[S:20][C:13]=23)=[C:7]([F:27])[CH:6]=1)[CH2:28][C:29]([OH:31])=[O:30]
Reactant: CCOC(=O)C(C(=O)OCC)C(Nc1ccc(Oc2ccnc3cc(-c4cn(C)cn4)sc23)c(F)c1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1cnc(-c2cc3nccc(Oc4ccc(NC(CC(=O)O)C(F)(F)F)cc4F)c3s2)c1
Yield: 36.9 %

Procedure:
A solution of 319 (490 mg, 0.84 mmol) and sodium hydroxide (338 mg, 8.44 mmol) in water (0.7 mL) and ethanol (3.4 mL) was stirred at room temperature for 48 h. The solvents were removed under reduced pressure and the residue was dissolved in water (20 mL). The solution was neutralized to pH 4 with a 3N HCl solution and the solid thus formed was filtered off, rinsed with water and dried. The solid was suspended in dry toluene (20 mL), heated to reflux for 1 h under continuous stirring, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent MeOH-dichloromethane, gradient 10:90 to 50:50) and the resulting solid was triturated in a mixture of dichloromethane, ethyl acetate and hexane, isolated by filtration, and dried under high vacuum to afford title compound 320 (150 mg, 0.31 mmol, 37% yield). LRMS (M+1) 480.9 (100%).
Reaction SMILES: C(OC([NH:11][NH:12][CH2:13][CH:14]1[O:28][C:17]2=[C:18]3[C:23](=[C:24]([CH3:26])[CH:25]=[C:16]2[CH2:15]1)[NH:22][C:21](=[O:27])[CH2:20][CH2:19]3)=O)C1C=CC=CC=1.[H][H]>CN(C)C=O.CO.Cl.CO.[Pd]>[NH:12]([CH2:13][CH:14]1[O:28][C:17]2=[C:18]3[C:23](=[C:24]([CH3:26])[CH:25]=[C:16]2[CH2:15]1)[NH:22][C:21](=[O:27])[CH2:20][CH2:19]3)[NH2:11]
Reactant: Cc1cc2c(c3c1NC(=O)CC3)OC(CNNC(=O)OCc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(CNN)C2
Yield: 88.6 %

Procedure:
The compound obtained in Example 339 (0.77 g, 2.0 mmol) was dissolved in a mixture of dimethylformamide (6 ml), methanol (11 ml), and 5% HCl-methanol solution (2 ml). To the resultant solution, 10% palladium-on-carbon (0.30 g) was added, followed by stirring at ambient temperature for 2 hours in the stream of hydrogen. The palladium-on-carbon was filtered off, and the solvent was distilled off under reduced pressure. 0.438 g of the title compound was obtained as pale yellow crystals (76.5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([Mg]Br)C.[CH3:15][C:16]1([CH3:24])[C:18]([CH3:20])([CH3:19])[CH:17]1[C:21](Cl)=[O:22]>ClCCl.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:21]([CH:17]1[C:18]([CH3:20])([CH3:19])[C:16]1([CH3:24])[CH3:15])=[O:22]
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: Brc1ccc2[nH]ccc2c1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3ccc(Br)cc23)C1(C)C
Yield: 37.7 %

Procedure:
A mixture of 5-bromoindole (5.0 g. 26 mmol), ethylmagnesium bromide (1.0 M solution in THF, 31 mL, 31 mmol), zinc chloride (1.0 M solution in Et2O, 31 mL, 31 mmol) and the product of Example 1A (38 mmol) in 100 mL of dichloromethane was processed as described in Example 1B to provide the title compound (3.1 g, 9.8 mmol, 38% yield). MS (DCI/NH3) m/z 321, 322 (M+H)+.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Cl:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=O>CO.Cl.O>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:10](=[N:1][NH:2][C:3](=[S:4])[NH2:5])[CH2:9][CH2:8][CH2:7][Cl:6])=[CH:17][CH:16]=1
Reactant: O=C(CCCCl)c1ccc(Cl)cc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=S)NN=C(CCCCl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
Thiosemicarbazide (9.11 g, 0.1 mol) was added under nitrogen to a solution of 4,4'-dichlorobutyrophenone (21.7 g, 0.1 mol) in 350 mL of methanol plus 27 mL of 1N HCl plus 25 mL of water and the reaction stirred at room temperature for 21 hours (overnight). The solid was collected by filtration and dried to give 20.23 g of a white solid. Recrystallization of the solid from isopropyl alcohol gave 8.37 g (29%) of the title compound as a light yellow solid, mp 125-126° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH2:10].ClCCl.[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[CH2:21][N:20]([CH3:26])[CH2:19][CH:18]2[C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>CN(C=O)C.C(OCC)(=O)C>[NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][S:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH:18]2[C:17]3[C:22](=[C:23]([Cl:25])[CH:24]=[C:15]([Cl:14])[CH:16]=3)[CH2:21][N:20]([CH3:26])[CH2:19]2)[CH:28]=1)(=[O:35])=[O:34]
Reactant: NCCOCCOCCN
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCN)c2)C1

Procedure:
To a 50-mL 3-necked round-bottom flask was added 2-(2-(2-aminoethoxy)ethoxy)ethanamine (3.2 g, 21.59 mmol, 21.09 equiv) and dichloromethane (DCM; 20 mL). This was followed by the addition of a solution of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (Intermediate 1.6) (400 mg, 1.02 mmol, 1.00 equiv) in DMF (5 mL) dropwise with stirring. The resulting solution was stirred for 5 h at which time it was diluted with 100 mL of ethyl acetate. The resulting mixture was washed successively with 2×10 mL of water and 1×10 mL of Brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 300 mg (58%) of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as a yellow oil.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:36])[S:4]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[S:18][C:17]([NH:19][C:20]([N:22]([CH:29]3[CH2:34][CH2:33][CH:32]([CH3:35])[CH2:31][CH2:30]3)[CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[O:21])=[N:16][CH:15]=2)[CH2:9][CH2:8]1)(=[O:6])=[O:5].[F:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1>>[CH3:2][N:3]([CH3:36])[S:4]([N:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]2[S:18][C:17]([NH:19][C:20]([N:22]([CH:23]3[CH2:28][CH2:27][N:26]([C:42](=[O:43])[C:41]4[CH:45]=[CH:46][C:38]([F:37])=[CH:39][CH:40]=4)[CH2:25][CH2:24]3)[CH:29]3[CH2:30][CH2:31][CH:32]([CH3:35])[CH2:33][CH2:34]3)=[O:21])=[N:16][CH:15]=2)[CH2:11][CH2:12]1)(=[O:5])=[O:6]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC1CCC(N(C(=O)Nc2ncc(CN3CCN(S(=O)(=O)N(C)C)CC3)s2)C2CCNCC2)CC1
Agent: Cl
Product: CC1CCC(N(C(=O)Nc2ncc(CN3CCN(S(=O)(=O)N(C)C)CC3)s2)C2CCN(C(=O)c3ccc(F)cc3)CC2)CC1
Yield: 72.3 %

Procedure:
Prepared as described in general procedure (N) using 4-{2-[3-(4-methyl-cyclohexyl)-3-piperidin-4-yl-ureido]-thiazol-5-ylmethyl}-piperazine-1-sulfonic acid dimethylamide hydrochloride (47 mg, 0.083 mmol), TEA (26 μL, 0.19 mmol) and 4-fluorobenzoyl chloride (10 μL, 0.083 mmol) to afford 39 mg (73%) of the desired product after purification.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[CH:12]1[CH2:14][CH:13]1[CH2:15][NH:16][C:17](=[O:19])[CH3:18].[CH2:20](B(O)O)[CH3:21].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[CH2:20]([C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[CH:12]1[CH2:14][CH:13]1[CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH3:21]
Reactant: CC(=O)NCC1CC1c1c(Br)ccc2nn(C)cc12
Reactant: CCB(O)O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1ccc2nn(C)cc2c1C1CC1CNC(C)=O
Temperature: 120 °C
Yield: 18.4 %

Procedure:
N-{[2-(5-Bromo-2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}acetamide (200 mg, 0.621 mmol) obtained in Example 29, ethylboronic acid (229 mg, 3.105 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (30.0 mg, 0.0621 mmol), potassium carbonate (206 mg, 1.49 mmol) and tris(dibenzylideneacetone)dipalladium(0) (29.3 mg, 0.0311 mmol) were added to N,N-dimethylformamide (3.1 mL), and the mixture was stirred under nitrogen atmosphere with heating at 120° C. for 1 day. The reaction solution was diluted with ethyl acetate, and filtered through celite. The obtained filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate=0/100→5/95), silica gel column chromatography (NH, methanol/ethyl acetate=0/100→20/80) and HPLC to give the title compound (31 mg, yield 18%).