Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[N:18][CH:19]=2)[N:3]=1.[CH3:27][O:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:27][O:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=[C:4]([C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[N:18][CH:19]=3)[N:3]=2)[CH:32]=[N:31][CH:30]=1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2nc(Cl)cc(N3CCOCC3)n2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: COc1cncc(-c2cc(N3CCOCC3)nc(-c3ccc(NC(=O)C(C)(C)C)nc3)n2)c1

Procedure:
A mixture of N-(5-(4-chloro-6-morpholinopyrimidin-2-yl)pyridine-2-yl)pivalamide (50 mg, 0.133 mmol), 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (94 mg, 0.399 mmol) and Pd(dppf)Cl2-CH2Cl2 (16 mg, 0.020 mmol) in 2 mL of dimethoxyethane:2 M Na2CO3 (3:1) is heated under microwave irradiation for 15 minutes at 130° C. (normal absorption, fixed hold time). The reaction mixture is partitioned between EtOAc (50 mL) and H2O (10 mL); the organic layer is separated, washed with brine (7 mL), dried over Na2SO4, filtered and concentrated. The residue thus obtained is used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1>CO.[Pd]>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)/C=C/c1cccc(O)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1cccc(O)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.1 %

Procedure:
To a solution of (E)-methyl 3-(3-hydroxyphenyl)acrylate (15.8 g) in methanol (150 mL) was added 10% palladium-activated carbon (1.50 g) and, under a hydrogen atmosphere, the mixture was stirred at room temperature for 5 hr. The reaction mixture was filtered to remove palladium carbon, and the filtrate was evaporated under reduced pressure to give the title compound (16.0 g) as a colorless oil. This compound was used for the next step without further purification.
Reaction SMILES: [Br:1]Br.[K+].[Br-].[F:5][C:6]1[C:7]2[N:8]([CH:12]=[CH:13][N:14]=2)[CH:9]=[CH:10][CH:11]=1.CC([O-])=O.[Na+]>CO.O>[Br:1][C:12]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:6]([F:5])[C:7]2=[N:14][CH:13]=1
Reactant: Fc1cccn2ccnc12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Fc1cccn2c(Br)cnc12
Reaction time: 0.03 h
Yield: 83 %

Procedure:
A solution of bromine in MeOH, saturated with KBr (0.86 M, 1.0 ml, 0.86 mmol) was added to a cooled, stirred solution of 8-fluoroimidazo[1,2-α]pyridine (118 mg, 0.86 mmol) and NaOAc (85 mg, 1.04 mmol) in methanol saturated with KBr (1.6 ml). After 2 min, the solution was poured into water (50 ml) and the resulting yellow solution extracted with CH2Cl2 (3×50 ml). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated in vacuo, yielding 3-bromo-8-fluoroimidazo[1,2-α]pyridine as a yellow solid (155 mg, 83%), used without further purification: δH (400 MHz, CDCl3) 6.86-6.91 (1H, m), 6.95-6.99 (1H, m), 7.65 (1H, s), 7.98 (1H, dd, J 0.8 and 6.7); m/z (ES+) 217 (100%, [MH]+), 215 (100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:14]1[CH2:13][CH2:12][C:11]2[C:17](=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=2)[CH2:16][CH2:15]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCNCC2
Reactant: O=Cc1ccccc1
Product: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCN(Cc1ccccc1)CC2

Procedure:
The title compound (115 mg) was prepared from 3-(4-fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 190) and benzaldehyde as in Example 35. MS (ESI): exact mass calculated for C23H26FN3, 363.21. found, m/z 364.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.58-7.55 (m, 2H), 7.53-7.51 (m, 3H), 7.37-7.33 (m, 2H), 7.31-7.27 (m, 2H), 4.52 (s, 2H), 4.34 (m, 1H), 3.80-3.75 (m, 1H), 3.68-3.64 (m, 1H), 3.35-3.16 (m, 4H), 2.83-2.80 (m, 2H), 1.38 (t, J=6.7 Hz, 6H).
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18](=[O:23])[C:19]([NH:21][NH2:22])=[O:20])[CH2:9][C@@H:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:2]=1.C1N=CN([C:35](N2C=NC=C2)=[O:36])C=1>C1COCC1>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18]([C:19]2[O:20][C:35](=[O:36])[NH:22][N:21]=2)=[O:23])[CH2:9][C@@H:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)C(=O)NN
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1n[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-hydrazinyl-2-oxoacetamido)-2-methylpentanoate, intermediate 24, (200 mg, 0.50 mmol) in THF (10 mL) is added CDI (86 mg, 0.53 mmol). The crude is stirred at room temperature for 4 hrs. The crude is heated to 60 deg C. for 30 mins. This reaction is quenched with water and diluted in EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered and concentrated. The crude residue is purified via HPLC MeCN/water (0.1% TFA) to give (2R,4S)-ethyl 5-(biphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamido)pentanoate (69 mg). HPLC retention time=1.79 minutes (condition A), MS 424.2 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.17 (d, J=7.1Hz, 3H), 1.22 (t, J=7.1Hz, 3H), 1.66 (ddd, J=14.3, 10.2, 3.8Hz, 1H), 2.02 (ddd, J=14.2, 10.0, 3.8Hz, 1H), 2.59 (m, 1H), 2.89 (dd, 1H), 2.96 (dd, 1H), 4.03-4.19 (q, 2H), 4.37-4.47 (m, 1H), 6.91 (d, J=8.8Hz, 1H), 7.25 (d, 1H), 7.28-7.35 (m, 1H), 7.40 (t, J=7.6Hz, 2H), 7.49-7.60 (m, 4H), 10.51 (br. s., 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[C:24]([O:32][C:33]([F:36])([F:35])[F:34])[CH:23]=1>>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:20][C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([O:8][C:9]3[S:10][C:11]4[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=4[N:13]=3)=[C:6]([Cl:19])[CH:5]=2)(=[O:30])=[O:29])=[C:24]([O:32][C:33]([F:35])([F:34])[F:36])[CH:23]=1
Reactant: Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Product: O=S(=O)(Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1)c1ccc(Br)cc1OC(F)(F)F

Procedure:
4-Bromo-N-[3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenyl]-2-trifluoromethoxy-benzenesulfonamide was synthesized (83%) from 3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (420) and 4-bromo-2-trifluoromethoxybenzenesulfonyl chloride (Maybridge) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 8.16 (d, J=2.2 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.91-7.87 (m, 2H), 7.68 (d, J=8.7 Hz, 1H), 7.47 (d, J=8.7, 2.2 Hz, 1H), 7.31 (s, 2H). MS (EI): m/z 645 (M−H).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:20](=[CH:21][CH:22]=2)[O:19][C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:12][C:11]3=[O:23])[CH:5]=[N:4]1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH:42]1[C:46]([C:47]2[CH:48]=[C:49]([C:59](O)=[O:60])[CH:50]=[C:51]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH:52]=2)=[N:45][N:44]=[N:43]1>O.CN(C=O)C>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:20](=[CH:21][CH:22]=2)[O:19][C:13]2([CH2:14][CH2:15][N:16]([C:59]([C:49]4[CH:50]=[C:51]([C:53]5[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=5)[CH:52]=[C:47]([C:46]5[NH:45][N:44]=[N:43][N:42]=5)[CH:48]=4)=[O:60])[CH2:17][CH2:18]2)[CH2:12][C:11]3=[O:23])[CH:5]=[N:4]1
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)cn1
Reactant: O=C(O)c1cc(-c2ccccc2)cc(-c2nnn[nH]2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(-c5ccccc5)cc(-c5nnn[nH]5)c4)CC2)O3)cn1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
6-(1-Methyl-1H-pyrazol-4-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (93 mg), 1-hydroxybenzotriazole monohydrate (36 mg), 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride (57 mg), triethylamine (0.73 mL) and water (1 mL) were added in that order to a DMF (3 mL) solution of 5-(tetrazol-5-yl)biphenyl-3-carboxylic acid (50 mg), and stirred at 90° C. for 2 hours and 30 minutes. Water was added to the reaction liquid, and the formed precipitate was taken out through filtration, washed with hexane/ethyl acetate=3/2, and dried to obtain the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.36 (1.0H, s), 8.13 (1.0H, s), 8.03 (1.0H, s), 7.85-7.77 (6.0H, m), 7.53 (2.0H, d, J=7.2 Hz), 7.44 (1.0H, t, J=7.2 Hz), 7.10 (1.0H, d, J=8.4 Hz), 4.40-4.22 (1.0H, m), 3.83 (3.0H, s), 3.65-3.20 (3.0H, m), 2.89 (2.0H, s), 2.15-2.05 (1.0H, m), 1.95-1.78 (3.0H, m). MS [M+H]+=546.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]12[CH2:14][CH2:13]1.[CH3:15][N:16]1[C:20]([C:21]#[N:22])=[CH:19][CH:18]=[C:17]1B(O)O.[F-].[K+]>>[F:11][C:9]1[CH:10]=[C:2]([C:17]2[N:16]([CH3:15])[C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH:3]=[C:4]2[C:8]=1[NH:7][C:6](=[O:12])[C:5]12[CH2:14][CH2:13]1
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: O=C1Nc2c(F)cc(Br)cc2C12CC2
Agent: [F-]
Agent: [K+]
Product: Cn1c(C#N)ccc1-c1cc(F)c2c(c1)C1(CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.9 %

Procedure:
5′-Bromo-7′-fluorospiro[cyclopropane-1,3′-indol]-2′(1′H)-one (0.60 g, 2.3 mmol), 1-methyl-5-cyano-2-pyrroleboronic acid (0.63 g, 4.2 mmol), KF (0.44 g, 7.6 mmol), and Pd2(dba)3 monochloroform adduct (60 mg, 0.058 mmol) were added to a vial and then purged with nitrogen. THF (5.5 mL) was added and the mixture was purged with nitrogen for 5 min. A solution of tri-t-butylphosphine (10% wt in hexanes) (0.342 mL, 0.115 mmol) was added via syringe and the mixture was stirred vigorously at 25° C. for 2.5 h. The mixture was diluted with 100 mL of EtOAc and filtered through a plug of silica gel and concentrated. Purification by flash chromatography (25% acetone/hexane) afforded the title compound (0.53 g, 83%) as a white solid. MP 228-231° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(N(CC)CC)C.[C:37]1([CH2:43][CH2:44][S:45][CH:46]([C:50](O)=[O:51])[C:47](O)=[O:48])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[OH:51][C:50]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[CH:10][CH:11]=2)[O:17][C:47](=[O:48])[C:46]=1[S:45][CH2:44][CH2:43][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(OCc2ccncc2)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1oc(-c2ccc(OCc3ccncc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(4-pyridinylmethoxy)acetophenone (2.00 g, 8.81 mmol), trimethylsilyltriflate (2.04 mL, 10.57 mmol), triethylamine (2.45 mL, 17.62 mmol), methylene chloride (22 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. dec. 212° C.; 1H NMR (400 MHz, DMSO-d6) δ2.73 (t, 2 H), 2.88 (t, 2 H), 5.29 (s, 2 H), 6.48 (s, 1 H), 7.18 (m, 5 H), 7.45 (d, 2 H), 7.74 (d, 2 H), 8.90 (d, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]1[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16][C@H:15]1[NH2:23])=[O:12])=[CH:5]2.[CH3:24][N:25]1[CH2:30][CH2:29][C:28]2[N:31]=[C:32]([C:34]([O-])=[O:35])[S:33][C:27]=2[CH2:26]1.[Li+].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O.CO.C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]1[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16][C@H:15]1[NH:23][C:34]([C:32]1[S:33][C:27]3[CH2:26][N:25]([CH3:24])[CH2:30][CH2:29][C:28]=3[N:31]=1)=[O:35])=[O:12])=[CH:5]2
Reactant: COC(=O)C1C[C@@H](N)[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)C1
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCO
Solvent: O
Product: COC(=O)C1C[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1R*,2R*)-N1-[(5-Chloroindol-2-yl)carbonyl]-4-methoxycarbonyl-1,2-cyclopentanediamine (mixture of stereoisomers) (3.42 g) was dissolved in N,N-dimethylformamide (20 ml), and lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (3.12 g), 1-hydroxybenzotriazole monohydrate (689 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.89 g) were added to stir the mixture overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate and dichloromethane were added to the residue to conduct liquid separation. The resultant water layer was extracted with dichloromethane. The resultant organic layers were collected and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography on silica gel (dichloromethane:methanol=97:3→19:1) to obtain Stereoisomer A (585 mg) and Stereoisomer B (1.31 g). Each stereoisomer was dissolved in methanol, and a 1N ethanol solution of hydrochloric acid was added thereto. After the solvent was distilled off under reduced pressure, ethyl acetate was added to the residue. Precipitate formed was collected by filtration to obtain the title compounds [Stereoisomer A (573 mg) and Stereoisomer B (1.26 g)] as pale yellow solids.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH:19]=1)[CH:17]=O>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH2:17][C:7]2[S:6][C:5]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[CH:8]=2)[CH:19]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: Cc1ccc2sccc2c1
Product: Cc1ccc2sc(Cc3cc(Br)ccc3Cl)cc2c1

Procedure:
5-Methylbenzo[b]thiophene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([CH3:15])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].Cl.[NH2:32][CH2:33][CH2:34][N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37].C[O-].[Na+]>CCO>[CH3:39][S:36]([N:35]([CH3:40])[CH2:34][CH2:33][NH:32][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([CH3:15])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4])(=[O:38])=[O:37]
Reactant: CN(CCN)S(C)(=O)=O
Reactant: COC(=O)c1nc(C)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(C(=O)NCCN(C)S(C)(=O)=O)c(O)c2cc(-c3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 140 °C
Yield: 34.9 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-8-methyl-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.088 mmol), N-(2-amino-ethyl)-N-methyl-methanesulfonamide HCl salt (83 mg, 0.44 mmol), and NaOMe (24 mg, 0.44 mmol) in EtOH (3 mL) was heated at 140° C. for 6 h in a microwave reactor. Solvent was evaporated in vacuo, and the residue was partitioned between EtOAc and 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The residue was purified twice by silica gel chromatography (first eluted with 0-2.5% MeOH/CH2Cl2, then with 15-100% EtOAc/hexanes+2% AcOH) to give 16 mg of the title compound as an off-white solid. MS: (+) m/z 521.28 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([N+:17]([O-])=O)[CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>[Fe].CCO.O>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[C:10]([CH3:20])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nn(Cc2ccccc2)c2cccc([N+](=O)[O-])c12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1nn(Cc2ccccc2)c2cccc(N)c12
Yield: 1020.3 %

Procedure:
A solution of 1-benzyl-3-methyl-4-nitro-1H-indazole (0.052 g, 0.19 mmol), ammonium chloride (0.0052 g, 0.097 mmol) in 4:1 EtOH/water (5 mL) was treated with iron (0.11 g, 1.9 mmol) and refluxed for 2 hours. The mixture was concentrated and residue shaken in EtOAc/water, filtered through GF/F paper, and concentrated to provide 1-benzyl-3-methyl-1H-indazol-4-amine (0.46 g, 82% yield) as a yellow gum.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(CCC2C=CC=CC=2)C=CC=CC=1.C1(CCC2C=CC(S(Cl)(=O)=O)=CC=2)C=CC(S(Cl)(=O)=[O:40])=CC=1.ClS(O)(=O)=O>>[C:1]1([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([S:7]([OH:40])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccc(CCc2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccc(CCc2ccccc2)cc1
Agent: O=S(=O)(O)Cl
Solvent: c1ccc(CCc2ccccc2)cc1
Product: O=S(=O)(O)c1ccc(CCc2ccccc2)cc1

Procedure:
Polybibenzyl sulfone homopolymers are prepared by heating bibenzyl- 4 -sulfonyl chloride in the presence of a catalytic amount of an anhydrous Lewis acid, or by using a stoichiometric mixture of bibenzyl and bibenzyl- 4,4' -disulfonyl chloride as hereinafter described. The preparation of the homopolymer first necessitates the synthesis of either the mono or di sulfonyl chloride derivative of bibenzyl. Bibenzyl- 4 -sulfonyl chloride may be prepared by a three step procedure by treating bibenzyl in solution with approximately equi molar quantities of chlorosulfonic acid to form bibenzyl- 4 -sulfonic acid followed by neutralization in an aqueous medium using sodium or barium hydroxide to yield the sodium or barium salt which is in turn treated in a solvent with an acid halide such as thionyl chloride to yield bibenzyl- 4 -sulfonyl chloride. Another suitable technique for the preparation of the monosulfonyl chloride derivative involves the treatment of the free sulfonic acid derivative of bibenzyl in a solvent with a complex of phosgene and a tertiary organic amide.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([N:14](S(C)(=O)=O)[S:15]([CH3:18])(=[O:17])=[O:16])[CH:5]=1.CC1C=CC(C(OC)=O)=C(NS(C)(=O)=O)C=1>CO>[CH3:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:5]=1
Reactant: COC(=O)c1ccc(C)cc1N(S(C)(=O)=O)S(C)(=O)=O
Agent: COC(=O)c1ccc(C)cc1NS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C(=O)O)c(NS(C)(=O)=O)c1

Procedure:
An aqueous solution of sodium hydroxide (11.0 g) was added to a solution of a mixture of methyl 4-methyl-2-(N,N-bis(methylsulphonyl)amino]benzoate and methyl 4-methyl-2-(N-methylsulphonylamino)benzoate (23.26 g) in methanol and the resulting suspension was heated at reflux for 1 hour. It was cooled and the methanol was removed by evaporation. The aqueous solution was acidified and the resultant solid was filtered off to give 4-methyl-2-(N-methylsulphonylamino)benzoic acid (16.42 g) as a cream solid, m.p. 202-205° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Cl:10][C:11]1[S:12][C:13]([Cl:22])=[CH:14][C:15]=1[S:16]([N:19]=[C:20]=[O:21])(=[O:18])=[O:17]>C(Cl)Cl>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:20]([NH:19][S:16]([C:15]2[CH:14]=[C:13]([Cl:22])[S:12][C:11]=2[Cl:10])(=[O:17])=[O:18])=[O:21])[N:3]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1cc(Cl)sc1Cl
Solvent: ClCCl
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2cc(Cl)sc2Cl)n1
Reaction time: 16 h

Procedure:
To a suspension of 12 g of 2-amino-4,6-dimethylpyrimidine in 300 ml of methylene chloride was added at ambient temperature 26 g of 2,5-dichloro-3-thiophenesulfonyl isocyanate. After stirring for 16 hours, the resulting solution was evaporated to dryness and the desired product, obtained as a solid residue, was triturated with ethyl ether and filtered. The solid product thus obtained melted at 192°-194° and showed infrared absorption peaks at 1550 cm-1, 1605 cm-1, and 1690 cm-1.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15]S(C)(=O)=O.[CH2:20]1[C:28]2[CH:27]=[CH:26][CH:25]=[C:24](O)[C:23]=2[CH2:22][CH2:21]1.[OH-].[K+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[CH2:20]1[C:28]2[C:23](=[C:24]([O:15][CH2:14][CH2:13][C:3]3[N:4]=[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[O:6][C:2]=3[CH3:1])[CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Reactant: Oc1cccc2c1CCC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1CCOc1cccc2c1CCC2
Temperature: 80 °C
Reaction time: 4 h
Yield: 107.9 %

Procedure:
4.00 g of methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester [PCT Int. Appl. (2000) WO0008002] (14.22 mmol), 2.00 g of 4-indanol (14.93 mmol) and 487.6 mg of tetrabutylammonium hydrogen sulfate were dissolved in 65 ml of toluene and heated to 80° C. KOH was then slowly added (10.66 ml of a 2M solution in H2O, 21.33 mmol), keeping the temperature at 75-80° C. The resulting mixture was stirred for 4 hours at 80° C. 35 ml of water were added, the mixture stirred for another 5 minutes at 80° C. and the water phase was then removed. 20 ml of water were added to the toluene phase, the mixture stirred for 5 minutes at 80° C., and the water phase removed. The water phase was extracted 3 times with dichloromethane. The combined organic phases were dried over MgSO4 and evaporated to afford 4.90 g (100%) of 4-[2-(indan-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole as brown solid.
Reaction SMILES: Cl.[OH:2][CH2:3][C@H:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1.CCN(C(C)C)C(C)C.[Br:29][CH2:30][C:31](Cl)=[O:32].O>C(Cl)Cl>[Br:29][CH2:30][C:31]([N:9]1[CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5][C@H:4]1[CH2:3][OH:2])=[O:32]
Reactant: O=C(Cl)CBr
Reactant: O=C(OCc1ccccc1)N1CCN[C@H](CO)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(OCc1ccccc1)N1CCN(C(=O)CBr)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
Benzyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate hydrochloride (0.83 g, 2.9 mmol) was dissolved in methylene chloride (10 mL) together with DIPEA (1.5 mL, 8.6 mmol). Bromoacetyl chloride (0.48 g, 3.0 mmol) was added at 0° C. by means of drops. The mixture was stirred at RT for 1 h and then water (10 mL) was added. The phases were separated by means of a phase separator column. The organic solution was collected and the solvent was removed by evaporation. There was obtained 1.1 g (100%) of benzyl (3S)-4-(bromoacetyl)-3-(hydroxymethyl)piperazine-1-carboxylate as a brown oil. LCMS: m/z 370 (M−1)−.