Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:22][CH2:21][C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)[CH3:2].[Sn](Cl)(Cl)(Cl)Cl.[CH3:28][CH:29]([CH2:35][CH2:36][CH2:37][CH:38]([CH3:50])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:49])[CH2:43][CH2:44][CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:30][CH2:31]CCO.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[CH2:21][O:22][C@H:5]1[O:4][CH2:1][CH2:2][CH2:31][CH2:30][CH:29]([CH3:28])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:50])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:49])[CH2:43][CH2:44][CH2:45][CH:46]([CH3:48])[CH3:47])(=[O:10])[CH3:9]
Reactant: CC(=O)O[C@@H]1OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCCCO
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OCCCCC(C)CCCC(C)CCCC(C)CCCC(C)C)OC[C@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 15.9 %

Procedure:
Under an argon atmosphere, 318 mg of β-xylose tetraacetate was dissolved in 6 ml of dry methylene chloride, and the solution was cooled to 0° C. A solution of 0.12 ml of tin tetrachloride dissolved in 1 ml of methylene chloride was added dropwise thereto, the mixture was agitated at room temperature for 20 minutes, and then cooled to −10° C. A solution of 326.6 mg of 5,9,13,17-tetramethyloctadecanol in 1 ml of methylene chloride was added dropwise thereto, and the mixture was agitated for 4 hours. A sodium bicarbonate water was added to the reaction solution and extraction was carried out 3 times with methylene chloride. The extract was washed with water and dried over anhydrous sodium sulfate. After the filtration, the resultant was concentrated, and the concentrate was purified by column chromatography to obtain 93 mg of 1-O-(5,9,13,17-tetramethyloctadecyl)-β-D-xylopyranoside triacetate.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:22][CH2:21]1.COCC(O)C.C(N(CC)C(C)C)(C)C>>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=5)[N:6]4[N:5]=3)=[CH:31][CH:30]=2)[CH2:22][CH2:21]1
Reactant: CN1CCN(CCOc2ccc(N)cc2)CC1
Reactant: CS(=O)c1ncc2ccc(-c3cccnc3)n2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: CN1CCN(CCOc2ccc(Nc3ncc4ccc(-c5cccnc5)n4n3)cc2)CC1

Procedure:
Into a microwave vial, 2-Methanesulfinyl-7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazine (0.104 g, 0.000404 mol), 4-[2-(4-Methyl-piperazin-1-yl)-ethoxy]-phenylamine (0.209 g, 0.000888 mol), 1-Methoxy-2-propanol (0.971 mL, 0.00993 mol) and N,N-Diisopropylethylamine (0.155 mL, 0.000888 mol) were added. The reaction was microwaved on 300 watts, 170° C. for 50 minutes. The solvent was removed under vacuum. The desired product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 12% methanol). The collected fractions afforded {4-[2-(4-Methyl-piperazin-1-yl)-ethoxy]-phenyl}-(7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine as a yellow solid (28 mg, 16%). MP 107-110° C. LCMS (E/I+) 430.8 (M+H). NMR 1H (DSMO-d6)-9.42 (d, 1H, J=2.00), 9.39 (s, 1H), 9.04 (s, 1H), 8.66 (d, 1H, J=7.76 Hz), 8.61 (d, 1H, J=6.56 Hz), 7.60-7.70 (m, 3H), 7.32 (d, 1H, J=4.77 Hz), 6.98 (d, 1H, J=4.76 Hz), 6.95 (d, 2H, J=9.00 Hz), 4.16 (t, 2H, J=5.26 Hz), 2.40-3.50 (m, 13H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C@H:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[C:4](=[O:13])[C:3]=1[C:14]#[N:15].[Br:16]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:16][C:7]1[C:2]([Cl:1])=[C:3]([C:14]#[N:15])[C:4](=[O:13])[N:5]([C@H:8]([CH:10]([CH3:11])[CH3:12])[CH3:9])[CH:6]=1
Reactant: CC(C)[C@H](C)n1ccc(Cl)c(C#N)c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[C@H](C)n1cc(Br)c(Cl)c(C#N)c1=O
Temperature: 50 °C
Reaction time: 20 h
Yield: 97.3 %

Procedure:
To a solution of 4-chloro-1-((2S)-3-methylbutan-2-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step E (14.6 g) in N,N-dimethylformamide (120 mL) was added N-bromosuccinimide (17.4 g), and the mixture was stirred at 50° C. for 20 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (19.2 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=O)=[C:9]([F:16])[CH:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:31][C:32]1[C:40]([NH2:41])=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([NH2:36])=[O:35]>N1C=CC=CC=1.CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]2[NH:41][C:40]3[CH:39]=[CH:38][CH:37]=[C:33]([C:34]([NH2:36])=[O:35])[C:32]=3[N:31]=2)=[C:9]([F:16])[CH:8]=1
Reactant: O=C(O)c1ccc(C2OCCCO2)cc1F
Reactant: NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: NC(=O)c1cccc2[nH]c(-c3ccc(C4OCCCO4)cc3F)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
A solution of EXAMPLE 22B (770 mg, 3.4 mmol) in pyridine (5 mL) and N,N′-dimethylformamide (10 mL) was treated with 1,1′-carbonyldiimidazole (763 mg, 3.4 mmol) at 40° C. for 30 minutes. 2,3-Diaminobenzamide dihydrochloride (826 mg, 5.1 mmol) was added and the mixture stirred at ambient temperature overnight. The mixture was concentrated and the residue refluxed overnight in 20 mL of xylene and 2 mL of acetic acid. After cooling and concentration, the residue was purified by flash chromatography on silica gel using ethyl acetate to give the title compound (550 mg, 50%). MS (DCI/NH3) m/z 342 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][CH:13]3[N:15](C)[CH:10]([CH2:11][CH2:12]3)[CH:9]=2)=[CH:4][CH:3]=1.ClC(OC(Cl)C)=O.[C:24]([OH:30])(=[O:29])[CH2:25][C:26]([OH:28])=[O:27]>ClCCCl.C(O)C>[C:24]([OH:30])(=[O:29])[CH2:25][C:26]([OH:28])=[O:27].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH:10]3[NH:15][CH:13]([CH2:12][CH2:11]3)[CH:14]=2)=[CH:6][CH:7]=1
Reactant: CN1C2C=C(c3ccc(Cl)cc3)CC1CC2
Agent: CC(Cl)OC(=O)Cl
Agent: O=C(O)CC(=O)O
Solvent: CCO
Solvent: ClCCCl
Product: Clc1ccc(C2=CC3CCC(C2)N3)cc1

Procedure:
To a stirred solution of 3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (2 g, 8.5 mmol) in anhydrous 1,2-dichloroethane (20 mL) under a nitrogen atmosphere was added 1-chloroethyl chloroformate (1.25 mL, 11.6 mmol). The reaction mixture was heated at reflux overnight, then added 1-chloroethyl chloroformate (1 mL, 9.3 mmol), once again the reaction mixture was heated at reflux overnight. The reaction mixture was concentrated to an oil, the oil was dissolved in methanol (25 mL), this solution was heated at reflux for 2 hours and then concentrated to an oil. The residue was dissolved in water and added concentrated NH4OH until pH=10, the water phase was extracted with diethyl ether. The organic phase was dried with magnesium sulphate and concentrated to dryness. The residue was chromatographed over silica gel (dichloromethane/acetone/methanol, 4/1/1 (v/v)). The product fractions was concentrated to an oil, the oil was dissolved in ethanol (96%) and malonic acid (0.55 g, 5.3 mmol) in ethanol (96%) was added, this solution was concentrated to an oil, the oil was trituated in diethyl ether, the title compound precipitated as powder and was isolated by filtration. Yield (1.32 g, 48%), m.p. 136.1-138° C.
Reaction SMILES: O1CCCC1.O1CCCC1.C([N-]C(C)C)(C)C.[Li+].[C:19]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH3:20].[O:27]1[CH2:31][CH:30]=[CH:29][C:28]1=[O:32]>O>[O:32]=[C:28]1[O:27][CH2:31][CH:30]([CH2:20][C:19]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:29]1
Reactant: O=C1C=CCO1
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1COC(=O)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Tetrahydrofuran (50 mL) and Lithium diisopropylamide mono tetrahydrofuran complex (20 mL of 1.5 M in cyclohexane) was cooled in a dry ice/Isopropanol bath for 10 min. Tert-butyl acetate (3.5 mL 26 mmoles) was added via syringe and stirred at −78° C. for 30 min. 2(5H)-Furanone (1.59 g, 19 mmoles) was added dropwise and the reaction was stirred for 1 h at −78° C. The reaction was poured into water and extracted with ether 2×150 mL The ether extracts were combined and washed with water 100 mL then brine 3×100 mL, dried and the ether removed under reduced pressure to give 2.74 g of product (72%). MS (ESI+) for C10H16O4 m/z 223 (M+Na)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7](/[CH:8]=[CH:9]/[C:10]#[N:11])=[CH:6][C:5]=1[C:14]1[NH:15][CH2:16][C:17]2[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:18]=2[N:19]=1)[CH3:2].C(O)(=[O:29])C>[Ni]>[NH2:11][CH2:10][CH2:9][CH2:8][C:7]1[CH:12]=[CH:13][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:14]2[NH:15][C:16](=[O:29])[C:17]3[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:18]=3[N:19]=2)[CH:6]=1
Reactant: CC(=O)O
Reactant: CCCc1nn(C)c2c1N=C(c1cc(/C=C/C#N)ccc1OCC)NC2
Agent: [Ni]
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(CCCN)ccc3OCC)nc12
Reaction time: 3 h
Yield: 38 %

Procedure:
A solution of (E)-4-ethoxy-3-(-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-5-yl)cinnamonitrile (0.25 g, 0.00064 mol) in glacial acetic acid (25 ml) was stirred with Raney nickel catalyst (25 mg) under hydrogen at room temperature and at 50 p.s.i. for 3 hours. The resulting mixture was filtered and the filtrate evaporated under vacuum. The residue was partitioned between saturated aqueous sodium carbonate solution (50 ml) and dichloromethane (30 ml), the layers separated and the aqueous phase further extracted with dichloromethane (2×30 ml). The organic solutions were combined, dried (Na2SO4) and evaported under vacuum to give a brown solid, crystallisation of which from hexane-ethyl acetate gave the title compound as fawn crystals (96 mg, 38%), m.p. 115°-117° C. Found C,65.29; H,7.35; N,18.66. C20H27N5O2 requires C,65.02; H,7.37; N,18.96%.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH:17](=O)[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20].C(Cl)Cl>CO>[N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[CH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[OH:20])[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)Cc1ccccc1-2
Reactant: O=Cc1ccccc1O
Solvent: ClCCl
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(c1)C(=Cc1ccccc1O)c1ccccc1-2
Temperature: 72 °C
Reaction time: 6 h

Procedure:
To a solution of 2-nitrofluorene (250 mg, 1.18 mmol) and salicylaldehyde (159 mg, 1.30 mmol) in 10 mL of methanol was added KF—Al2O3 (170 mg, 1.06 mmol). The resulting mixture was stirred at 72° C. After 6 hrs, TLC indicated that the starting material was gone. 40 mL of CH2Cl2 was added into the reaction mixture. The insoluble solid was filtrated, and the filtrate was concentrated under vacuum to give a yellow solid, which was purified by silica gel column; eluting with 11% EtOAc in hexane afforded 125 mg of CYD-1-87 as a yellow solid. 1H-NMR (600 MHz, CDCl3) δ 10.05 (br s, 1H), 8.39 (s, 1H), 8.27 (dd, 1H, J=2.4 Hz, 8.4 Hz), 8.16 (d, 1H, J=8.4 Hz), 8.09 (m, 2H), 8.04 (s, 1H), 7.52 (m, 3H), 7.37 (m, 1H), 7.05 (d, 1H, J=8.4 Hz), 6.96 (t, 1H, J=7.2 Hz).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O.[CH3:12][C:13]([CH3:15])=[O:14]>O.CCO>[Cl:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1/[CH:6]=[CH:12]/[C:13](=[O:14])/[CH:15]=[CH:6]/[C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[Cl:3]
Reactant: O=Cc1ccccc1Cl
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(/C=C/c1ccccc1Cl)/C=C/c1ccccc1Cl
Yield: 67.8 %

Procedure:
A solution of NaOH (1.4 g, 142 mmol) in H2O (60 mL) and EtOH (60 mL) was added to a mixture of 2-chlorobenzaldehyde (8 mL, 72 mmol) in acetone (2.6 mL, 36 mmol). The reaction mixture was stirred for 1d at room temperature and the resulting precipitate was filtered, washed with H2O, recrystallized from EtOAc and dried in vacuo to obtain NW268 as a bright yellow solid (7.4 g, 69%). mp: 107-109° C. 1H NMR (250 MHz, CDCl3) δ (ppm): 8.15 (d, 3J=16.0 Hz, 2H, Hvin), 7.79-7.66 (m, 2H, HAr), 7.51-7.29 (m, 6H, HAr), 7.08 (d, 3J=16.0 Hz, 2H, Hvin). 13C NMR (75 MHz, CDCl3) δ (ppm): 188.7 (C), 139.3 (CH), 135.4 (C), 133.0 (C), 131.2 (CH), 130.2 (CH), 127.7 (CH), 127.5 (CH), 127.1 (CH). MS (FAB) m/z: 303.1 (M+). Anal. calcd for C17H12Cl2O: C, 67.35; H, 3.99; Cl, 23.39. Found: C, 67.09; H, 4.06; Cl, 22.65%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](Cl)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH2:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH:19][C:12](=[O:13])[CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COC(CN)OC
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)NCC(OC)OC)cc1OC
Reaction time: 1 h

Procedure:
While cooling with ice, a solution of 3,4-dimethoxyphenylacetic acid chloride (485.2 g) in methylene chloride (1.1 liters) is added dropwise at 15°-20° C. to a solution of aminoacetaldehyde dimethylacetal (246.2 ml) and triethylamine (315 ml) in methylene chloride (2.2 liters) and the resulting mixture is stirred for 1 hour at 16°-18° C. It is then extracted several times with water, dried over magnesium sulphate and concentrated by evaporation. The resulting oil slowly crystallizes out.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O>C(OCC)(=O)C.CO.[Pd]>[NH:12]1[C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][CH2:4][C:3]1=[O:2]
Reactant: COC(=O)CNc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CNc2ccccc2N1
Yield: 99.4 %

Procedure:
A solution of N-(2-nitrophenyl)glycine methyl ester (740 mg, 3.6 mmol) in ethyl acetate (50 ml) and methanol (25 ml) was hydrogenated at atmospheric pressure over a catalytic amount of 10% palladium on carbon. After 1 h the mixture was filtered and reduced to afford 1,2,3,4-tetrahydroquinoxalin-2-one as a yellow solid (530 mg, 99%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][S:19][CH2:20][CH2:21][CH3:22])(=[O:4])[CH2:2][CH3:3].[NH2:23][C:24]1[C:25]([CH3:30])=[CH:26][CH:27]=[CH:28][CH:29]=1>C(#N)C>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][S:19][CH2:20][CH2:21][CH3:22])(=[O:4])[CH2:2][CH3:3]
Reactant: Cc1ccccc1N
Reactant: CCCSCCOc1cccc2c(Cl)c(C(=O)CC)cnc12
Solvent: CC#N
Product: CCCSCCOc1cccc2c(Nc3ccccc3C)c(C(=O)CC)cnc12
Yield: 59.5 %

Procedure:
3-Propanoyl-4-chloro-8-(2-propylthioethoxy)quinoline (2.5 g, 7.40 mmol) and o-toluidine (0.95 g, 8.86 mmol) was refluxed in acetonitrile (10 ml) for 2 h. The solvent was evaporated and the residue was partitioned between methylene chloride and 10% Na2CO3 solution. The organic layer was dried over Na2SO4 and evaporated. The crude product was purified by column chromatography (methylene chloride:ethyl acetate 80:20). 1.8 g (60%) of the title compound was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:36](Cl)=[O:37]>>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:9]([CH3:8])[C:36]([C:32]4[S:31][CH:35]=[CH:34][CH:33]=4)=[O:37])[CH:12]=3)=[CH:22][CH:21]=2)[S:28]1
Reactant: O=C(Cl)c1cccs1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)c1cccs1

Procedure:
In a manner similar to that of Example 37(e), by reacting 1 g (2.2 mmol) of 5-(3′-methylaminomethyl-biphenyl-4-ylmethyl)thiazolidine-2,4-dione trifluoro-acetate with 200 μl (2.5 mmol) of 2-thiophenecarboxylic acid chloride, and after purification, 500 mg (50%) of N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylthiophene-2-carboxamide are obtained in the form of a white solid with a melting point of 160° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:14]=[N+]=[N-].[Na+].[OH-].[Na+]>C(O)(=O)C.S(=O)(=O)(O)O>[C:1]1([N:7]2[CH:12]=[CH:11][NH:14][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCN(c2ccccc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C1C=CN(c2ccccc2)C=CN1
Temperature: 25 °C
Reaction time: 17 h
Yield: 92.8 %

Procedure:
To the product from Step A (12.54 g, 71.56 mmols) in glacial acetic acid (60 mL) and concentrated sulfuric acid (30 mL) at 0° C. was added sodium azide (5.12 g, 78.7 mmols) in five portions of 1.024 g over a period of 4 hours. The resultant pale yellow mixture was allowed to warm to room temperature with stirring under nitrogen for 17 hours. The mixture was poured onto ice and neutralized to pH 7 with 5 M aq. NaOH. The product was extracted into methylene chloride (2×400 mL) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated to a pale yellow solid. Flash chromatography purification eluting with EtOAc gradient to EtOAc/MeOH (95:5) yielded 12.37 g (91%) of the title intermediate as a pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=O.[CH2:7]([NH2:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[CH2:7]([NH:13][C:4](=[O:6])[CH2:3][CH2:2][NH2:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCN
Reactant: NCCC(=O)O
Product: CCCCCCNC(=O)CCN

Procedure:
As above using β-alanine in place of glycine and n-hexylamine in place of n-heptylamine.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([N:13]=[N:14][C:15]1(Cl)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:12])([CH3:11])[CH3:10]>CCOCC>[C:9]([N:13]=[N:14][C:15]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)N=NC1(Cl)CCCCC1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Product: CC(C)(C)N=NC1(c2ccccc2)CCCCC1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a clean, dry 250 ml. round bottom 4 nech flask equipped with a magnetic stirrer, thermometer, condenser and addition funnel, which was being purged with nitrogen, was added an ether solution containing 0.06 moles of phenylmagnesium bromide. The solution was cooled to 5° C. and a solution of 8.7 g. (0.043 moles) of 1-t-butylazo-1-chlorocyclohexane in 50 ml. of ether was added dropwise over 1/2 hour. After the addition was complete, the reaction was stirred for 15 minutes at room temperature and the excess phenylmagnesium bromide destroyed by the addition of wet ether. The reaction mixture was poured into 200 ml. of cold water and the ether layer separated, washed with 5% HCL, saturated sodium bicarbonate solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the ether removed on a rotating evaporator leaving 9.75 g. (93%) of a yellow liquid. The infrared spectrum of the product was in agreement with the structure of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:11](=[O:21])(=[O:20])[C:12]3[CH:19]=[CH:18][S:17][C:13]=3[N:14]([CH3:16])[N:15]=2)=[O:9])=[CH:4][CH:3]=1.CN(C=O)C.[Br:29]N1C(=O)CCC1=O>C(Cl)Cl>[Br:29][C:18]1[S:17][C:13]2[N:14]([CH3:16])[N:15]=[C:10]([C:8]([NH:7][CH2:6][C:5]3[CH:22]=[CH:23][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:9])[S:11](=[O:21])(=[O:20])[C:12]=2[CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1N=C(C(=O)NCc2ccc(Cl)cc2)S(=O)(=O)c2ccsc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1N=C(C(=O)NCc2ccc(Cl)cc2)S(=O)(=O)c2cc(Br)sc21

Procedure:
A solution containing N-(4-chlorobenzyl)-1-methyl-1H-thieno[2,3-e][1,3,4]-thiadiazine-3-carboxamide 4,4-dioxide (Preparation 56, 0.14 g) and anhydrous DMF (2 mL) is stirred under nitrogen while adding N-bromosuccinimide (0.074 g) in one portion. This solution is stirred overnight at room temperature before diluting with CH2Cl2 (50 mL) and washing with water (60 mL). The organic portion is separated and washed with brine, dried over Na2SO4, filtered, and concentrated to give a brown oil. Physical characteristics: MS (ESI+) m/z 448 (M+H)+, 450.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([CH2:24]O)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[N:4]=1)[CH3:2].CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+].[N:45]1([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>C(Cl)Cl.CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([CH2:24][N:48]4[CH2:49][CH2:50][N:45]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:46][CH2:47]4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[N:4]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CO)ccn34)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CN5CCN(C(=O)OC(C)(C)C)CC5)ccn34)c12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
To N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxamide (40 mg, 0.091 mmol) in DCM (3 mL) was added methanesulfonyl chloride (21 mg, 0.18 mmol). The reaction mixture was stirred for 30 minutes, diluted with DCM (10 mL), washed with saturated NaHCO3 aqueous solution (3 mL) and brine (3 mL). The organic phase was concentrated under reduced pressure to a residue, to which was added DMF (2 mL), K2CO3 (38 mg, 0.27 mmol) and tert-butyl piperazine-1-carboxylate (51 mg, 0.27 mmol). The reaction mixture was heated to 50° C. for 2 hours. The mixture was concentrated under reduced pressure to remove DMF. Silica gel chromatography (DCM/MeOH) gave the product (22 mg).