Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[S:21][C:6]2[NH:7][C:8](=[O:20])[N:9]([C@@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[C:10](=[O:11])[C:5]=2[C:4]=1[CH3:22].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[N:41]=[C:40](C(Cl)(Cl)Cl)[O:39][N:38]=2)=[CH:27][CH:26]=1.C(=O)([O-])[O-:47].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[S:21][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:47])[O:39][N:38]=4)=[CH:27][CH:26]=3)[C:8](=[O:20])[N:9]([C@@H:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH3:13])[C:10](=[O:11])[C:5]=2[C:4]=1[CH3:22]
Reactant: O=C([O-])[O-]
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: COc1sc2[nH]c(=O)n([C@H](C)c3ccccc3)c(=O)c2c1C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1sc2c(c1C)c(=O)n([C@H](C)c1ccccc1)c(=O)n2Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A mixture of 6-methoxy-5-methyl-3-[(1R)-1-phenylethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.62 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.97 g), potassium carbonate (0.54 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (4 mL) and methanol (4 mL). 1N Aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.0 g, 91%).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][CH:13]=[CH:14][C:15](=[O:17])[CH3:16].[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[OH:23][C:18]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:16][C:15](=[O:17])[CH:14]=[CH:13][O:12][CH3:11]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC=CC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC=CC(=O)C=C(O)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
LiHMDS (1M in THF, 100 mL, 2 eq) is added dropwise to a cold (−78° C.) solution of 4-methoxy-3-buten-2-one (10 mL, 100 mmol, 2 eq) in THF (400 mL). After a 30 min stirring at −78° C., a solution of pivaloyl chloride (6.12 mL, 50 mmol) in THF (100 mL) is added. The resulting mixture is allowed to warm to rt over 2 h and quenched by addition of a saturated solution of NH4Cl. THF is removed under vacuum. The concentrated mixture is extracted with Et2O. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (Hex/EtOAc, 1:0→85:15) to afford 6.83 g of the title compound as a yellow oil: ESI-MS: 185.1 [M+H]+; TLC: Rf=0.87 (Hex/EtOAc, 1:1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:26]2[CH2:30][CH2:29][CH2:28][S:27]2(=[O:32])=[O:31])[CH:3]=1.[CH3:33][C@@H:34]1[O:38][C:37](=[O:39])[NH:36][CH2:35]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:36]5[CH2:35][C@H:34]([CH3:33])[O:38][C:37]5=[O:39])=[CH:3][C:4]=4[N:26]4[CH2:30][CH2:29][CH2:28][S:27]4(=[O:32])=[O:31])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: C[C@H]1CNC(=O)O1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2N2CCCS2(=O)=O)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C[C@H](C)OC3=O)cc2N2CCCS2(=O)=O)CC1
Yield: 84.8 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (519 mg) described in Preparation Example 179 and (S)-5-methyloxazolidin-2-one (121 mg) described in Preparation Example 42, the title compound (457 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CN=C1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][O:15][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc(-c2ccc(Br)cc2)cc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
(4′-Bromobiphenyl-4-yl)methanol (0.70 g, 2.7 mmol) and imidazole (0.54 g, 8.0 mmol) were dissolved in tetrahydrofuran (20 mL), and tert-butyldimethylchlorosilane (1.2 g, 8.0 mmol) was added under a nitrogen atmosphere, followed by stirring at room temperature for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate, and subsequently washed sequentially with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous sodium chloride solution. After the organic layer was concentrated under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.90 (hexane/ethyl acetate=9/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.92 g, 2.4 mmol) as a white solid (yield 91%).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9]([CH2:19][N+:20]#[C-:21])([C:12]1[CH:18]=[CH:17][C:15](C)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[C-:22]#N.[Na+]>>[C:2]1([C@H:1]2[O:8][CH:21]=[N:20][C@@H:19]2[S:9]([C:12]2[C:13]([CH3:22])=[CH:14][CH:15]=[CH:17][CH:18]=2)(=[O:10])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: O=Cc1ccccc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Product: Cc1ccccc1S(=O)(=O)[C@H]1N=CO[C@@H]1c1ccccc1

Procedure:
In a manner analogous to Preparation 1, benzaldehyde (0.41 mL, 4.03 mmol), tosylmethylisocyanide (0.75 g, 3.84 mmol) and NaCN (0.02 g, 0.40 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 302.2 (M+H+).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10].[I:16]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1>[F:6][C:7]1[C:14]([I:16])=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: Cc1ccc(C#N)c(F)c1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C#N)c(F)c1I
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,2,6,6-tetramethyl-4-piperidine (TMP) (45 mL, 267 mmol) in THF (400 mL) was cooled to −78° C. under an atmosphere of nitrogen. n-Butyl lithium (2.5 M in hexane, 110 mL, 275 mmol) was added slowly maintaining the temperature below −70° C. After addition, the reaction mixture was warmed to −50° C. and stirred for 30 minutes. The clear solution became turbid indicating the salt formation. The reaction mixture was recooled to −80° C., and a solution of 2-fluoro-4-methylbenzonitrile (32.4 g, 240 mmol) in THF (150 mL) was slowly added maintaining temperature below −70° C. The mixture was then warmed to −50° C. and stirred for 30 minutes. The mixture was recooled to −70° C. and a saturated solution of iodine (67 g, 264 mmol) in THF (150 mL) was added slowly maintaining the temperature at −70° C. After addition, the mixture was warmed to ambient temperature. The reaction mixture was poured into a solution of Na2S2O3 (160 g in 1.5 L of water) and stirred for 1 h. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na2SO4, and filtered. The volatiles were evaporated under reduced pressure. The crude product was subjected to vacuum distillation, and at about 60° C., the excess TMP was removed, at about 100° C., the starting compound 2-fluoro-4-methylbenzonitrile and a small amount of 2-fluoro-3-iodo-4-methylbenzonitrile were removed and, finally at 115° C., pure 2-fluoro-3-iodo-4-methylbenzonitrile was obtained as an off-white amorphous solid. MS (ESI, pos. ion) m/z: 261.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:27][C:15]2[CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19][C:14]=2[C:13]=1[C:28](=[O:30])[NH2:29].C(N(CC)CC)C>O1CCCC1>[C:28]([C:13]1[C:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][C:15]=2[S:27][C:12]=1[NH:11][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:10])(=[O:30])[NH2:29]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc(N)c2C(N)=O)C1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2c(sc(NC(=O)Nc3ccc(Cl)cc3)c2C(N)=O)C1
Yield: 85.5 %

Procedure:
A solution of 4-chlorophenyl isocyanate (11.1 g, 72.3 mmol), compound A2 (19.5 g, 65.6 mmol), and triethylamine (12.0 mL, 86.1 mmol) in anhydrous tetrahydrofuran (150 mL) was stirred at room temperature for 16 h. After this time, the reaction mixture was concentrated under reduced pressure. The resulting residue was triturated with a mixture of 1:1 methylene chloride and ethyl acetate to afford compound A3 as an off-white solid (25.3 g, 86%): 1H NMR (300 MHz, DMSO-d6) δ 10.85 (s, 1H), 10.20 (s, 1H), 7.52-7.45 (m, 3H), 7.34 (d, J=9.0 Hz, 2H), 6.94 (bs, 1H), 4.43 (s, 2H), 3.57-3.53 (m, 2H), 2.79-2.75 (m, 2H), 1.43 (s, 9H). MS (M+Na) 473.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([P:11](=[O:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[I:51]I>O1CCCC1>[I:51][C:4]1[C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=[CH:6][C:5]=1[P:11](=[O:24])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: II
Reactant: COc1ccc(P(=O)(c2ccccc2)c2ccccc2)cc1OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(P(=O)(c2ccccc2)c2ccccc2)c(I)c1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
db) 3.38 g (10 mmol) of (3,4-dimethoxyphenyl)diphenylphosphine oxide and 50 ml of dry tetrahydrofuran were placed in a 0.3 l four-necked sulphonation flask provided with a stirrer, thermometer, dropping funnel and argon gasification. In a separate Schlenk tube 8.0 ml of 1.6N butyllithium solution in hexane (12.8 mmol) were added dropwise under argon and while stirring at -78° C. to a solution of 1.57 g (15.5 mmol) of diisopropylamine in 10 ml of tetrahydrofuran and the solution was stirred at 0° C. for a further 10 minutes. The thus-prepared lithium diisopropylamide solution was then transferred into the dropping funnel of the reaction apparatus and then added dropwise at about -75° C. to the (3,4-dimethoxyphenyl)-diphenylphosphine oxide solution. The resulting pink suspension was stirred at -78° C. for a further 2 hours. Then, it was treated dropwise at <-70° C. with a solution of 3.3 g (13 mmol) of iodine in 20 ml of tetrahydrofuran. Towards the end of the addition there formed a viscous paste which was difficult to stir and which again dissolved when subsequently left to warm to room temperature. The reaction solution was washed 3 times with 20 ml of saturated Na2S2O3 solution each time and once with saturated NaCl solution, dried over Na2SO4, filtered and evaporated. The residue (5 g) was chromatographed on 200 g of silica gel with ethyl acetate and the resulting product was recrystallized from tert.-butyl methyl ether. There were obtained 3.8 g of (2-iodo-3,4-dimethoxyphenyl)-diphenylphosphine oxide as a light beige crystallizate : m.p. 178.5°-179.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:49]=[CH:48][C:20]([C:21]([N:23]([CH3:47])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]4C(=O)C5=CC=CC=C5C4=O)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.O.NN>C(O)C.C(OCC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:47])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=[O:22])=[CH:48][CH:49]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCCCN3C(=O)c4ccccc4C3=O)cc2)cc1
Agent: NN
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCCCN)cc2)cc1

Procedure:
A suspension of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(5-phthalimidopentyloxy)phenyl]benzamide (1.1 g) in ethanol (20 ml) was stirred rapidly and treated with hydrazine hydrate (844 mg). The mixture was stirred at 60° C. for 3 hours. After cooling, the reaction mixture was diluted with diethyl ether and filtered through Celite. The Celite was washed with diethyl ether, and the filtrate was concentrated. The residual milky oil was again dissolved in diethyl ether, filtered through Celite, washed with diethyl ether, and concentrated to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(5-aminopentyloxy)phenyl]benzamide
Reaction SMILES: N1[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].ClCC1[CH:23]=[CH:22][C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[N:16]=2)=[C:12]([O:24][CH3:25])[CH:11]=1.[CH3:26][N:27](C=O)[CH3:28]>>[F:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:13]2[CH:22]=[CH:23][C:5]([CH2:4][N:3]3[CH:28]=[N:27][CH:26]=[N:2]3)=[CH:11][C:12]=2[O:24][CH3:25])[N:16]=1
Reactant: COc1cc(CCl)ccc1Oc1cccc(F)n1
Reactant: c1c[nH]nn1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1cc(Cn2cncn2)ccc1Oc1cccc(F)n1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of triazole (18 mg; 0.267 mmol) and NaH (10 mg; 0.25 mmol) in DMF (1 mL), under argon, was added a solution of 2-[4-(chloromethyl)-2-methoxyphenoxy]-6-fluoropyridine (65 mg; 0.243 mmol) in DMF (1 mL). The reaction mixture was allowed to stir overnight at 40° C. After concentration, the reaction was hydrolysed with saturated NH4Cl (1 mL), extracted with AcOEt (2*1 mL). Combined organic phases were dried over Na2SO4, concentrated in vacuo, the title compound (72 mg; quantitative) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:13].Cl[C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl>[CH3:12][C:8]1([CH3:11])[CH2:7][C:6]2[CH:5]=[CH:4][C:3]([CH3:13])=[C:2]([N:1]=[C:15]=[O:17])[C:10]=2[O:9]1
Reactant: Cc1ccc2c(c1N)OC(C)(C)C2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1N=C=O)OC(C)(C)C2
Temperature: 80 °C

Procedure:
A 400 mg amount of 7-amino -2,2,6-trimethyl-2,3-dihydrobenzofuran was dissolved in 10 ml of carbon tetrachloride, and 246 mg of triphosgene was added thereto. The reaction solution was heated to 80° C., and 229 mg of triethylamine was slowly added thereto with stirring. Further, the mixture was heated under reflux for 1.5 hr. The reaction mixture was filtered through Celite to remove insolubles. The solvent was removed by evaporation to provide 461 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>C(Cl)Cl.CO>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][N:26]3[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]3)=[CH:36][CH:35]=2)=[N:3][CH:4]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)cc2)CC1
Yield: 62 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-((2,5-dichloropyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide and 4-((4-methylpiperazin-1-yl)methyl)aniline in 62% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.53 (d, 1H, J=8.2 Hz), 8.11 (s, 1H), 7.84 (dd, 1H, J=8.2, 1.3 Hz), 7.54 (m, 1H), 7.45 (d, 2H, J=8.2 Hz), 7.22 (m, 3H), 3.47 (s, 2H), 2.72 (s, 6H), 2.48 (bs, 8H), 2.29 (s, 3H); MS (ESI): 516.3 [M+H]+, 258.8 [M+2H]2+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-])=O.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C.Br[CH2:29][C:30](OC)=[O:31]>C(Cl)Cl>[N:15]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]3[O:1][CH2:29][C:30](=[O:31])[NH:12][C:3]=3[CH:4]=2)(=[O:10])=[O:9])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1O
Reactant: COC(=O)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1COc2ccc(S(=O)(=O)N3CCCCC3)cc2N1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
To a 15 mL screw cap vial was added 4-hydroxy-3-nitrobenzene-1-sulfonyl chloride (238 mg, 1.0 mmol) and piperidine (102 mg, 1.2 mmol) in DCM (5.0 mL) followed by triethylamine (346 μL, 2.5 mmol). After stirring at 23° C. for 1 h, the reaction was concentrated in vacuo and the resulting residue was taken up in sat aqueous NaHCO3. The resulting solid was isolated by filtration, washed with water and dried in vacuo to give a white solid. The material was subsequently alkylated using the general procedure for alkylation of substituted 2-nitrophenols using methyl bromoacetate as the alkylating agent followed by treatment in the general procedure for reduction of nitro group and subsequent ring closure to give the title compound as a white solid: 1H NMR (DMSO-d6, 400 MHz): δ=10.91 (s, 1H), 7.21-7.32 (m, 2H), 7.15 (d, J=8.1 Hz, 1H), 4.71 (s, 2H), 2.85 (t, J=5.1 Hz, 4H), 1.46-1.62 (m, 4H), 1.37 ppm (d, J=5.1 Hz, 2H). ESI-MS: m/z 297.1 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].I[C:8]1[CH:9]=[N:10][N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:32]1([C:8]2[CH:9]=[N:10][N:11]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Ic1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Yield: 59.6 %

Procedure:
Trityl chloride (1.58 g, 5.67 mmol) was added to a stirred cold (0-5° C.) solution of 4-iodo pyrazole (1 g, 5.15 mmol) and triethylamine (1.04 g, 10.3 mmol) in DCM (12 mL). Stirring was continued at room temperature overnight. Cold water was then added and the product was extracted with DCM and the organic layer was washed with saturated sodium bicarbonate solution followed by brine. The organic phase collected was dried over Na2SO4 and concentrated under reduced pressure The residue was purified by column chromatography (using neutral alumina and 2% EtOAc in hexane as eluent) to afford 1.9 g (84.4% Yield) of 4-iodo-1-trityl-1H-pyrazole. Na2CO3 (727 mg, 6.86 mmol) was added to a stirred solution of 4-iodo-1-trityl-1H-pyrazole (1.5 g, 3.43 mmol) in toluene: H2O (4:1, 20 mL). Pd(PPh3)4 (790 mg, 0.686 mmol) and phenylboronic acid (838 mg, 6.86 mmol) were then added and the reaction mixture was heated to reflux for 2 hrs. The reaction mixture was then diluted with water and the product was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulfate and concentrated to in vacuo. Purification by column chromatography (using neutral alumina and 5% EtOAc in hexane as eluent) afforded 790 mg (59.4% Yield) of 4-phenyl-1-trityl-1H-pyrazole. 1H NMR (300 MHz, CDCl3): δ 7.96-7.94 (s, 1H), 7.64-7.6 (s, 1H), 7.46-7.4 (d, 2H), 7.36-7.0 (m, 11H), 7.24-7.16 (m, 7H). A solution of 4-phenyl-1-trityl-1H-pyrazole (785 mg, 2.03 mmol) in ether.HCl (15 mL) was stirred for 1 hr. The reaction mixture was then concentrated under reduced pressure and washed with hexane to afford 320 mg (87.4% Yield) of 4-phenyl-1H-pyrazole hydrochloride. 1H NMR (300 MHz, DMSO-d6): δ 8.1-8.08 (s, 2H), 7.64 (d, 2H), 7.38 (t, 2H), 7.22 (t, 1H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.C(Cl)[Cl:37]>>[ClH:37].[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: ClCCl
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: C1CN(C2CCC3(CC2)OCCO3)CCO1
Product: Cl
Yield: 80 %

Procedure:
A solution of 1,4-dioxa-spiro[4.5]decan-8-one (5.00 g, 32.0 mmol) in CH2Cl2 (100 mL) was treated with morpholine (2.79 mL, 32.0 mmol), NaBH(OAc)3 (9.50 g, 44.8 mmol), and acetic acid (1.84 mL, 32.0 mmol) at RT for 4 h. The mixture was quenched with NaOH (75 mL, 2N aq) and extracted with ether (3×150 mL). The combined organic layers were washed with water (1×100 mL) and brine (1×100 mL), dried over MgSO4, and concentrated in vacuo to about 100 mL volume. HCl (9 mL, 4N in dioxane) was added dropwise with stirring. The resulting precipitate was filtered, rinsed with ether, and air-dried to afford the title compound (6.79 g, 80%) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 4.13-4.05 (m, 2H), 3.90-3.80 (m, 2H), 3.54-3.46 (m, 2H), 3.32-3.17 (m, 3H), 2.23-2.14 (m, 2H), 1.95-1.75 (m, 4H), 1.72-1.61 (m, 2H).