Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[Cl:15])[NH:7][C:6]=2[N:5]=[C:4]([NH:16]C(=O)C(C)(C)C)[N:3]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([NH:29][CH3:30])=[CH:27][CH:26]=1.C(O)(C)C>Cl.CC(C)=O.CO>[Cl:15][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[C:14]1[C:2]([N:29]([C:28]3[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[CH3:30])=[N:3][C:4]([NH2:16])=[N:5][C:6]=1[NH:7]2
Reactant: CNc1ccc(OC)cc1
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)c2c(n1)[nH]c1cccc(Cl)c12
Agent: Cl
Solvent: CO
Solvent: CC(C)=O
Solvent: CC(C)O
Product: COc1ccc(N(C)c2nc(N)nc3[nH]c4cccc(Cl)c4c23)cc1
Temperature: 115 °C
Yield: 69 %

Procedure:
To 10 (20 mg, 0.06 mmol) was added 4-methoxy-N-methyl aniline (61 mg, 0.44 mmol), 50 mL of Isopropanol, and 4 drops of conc. HCl in a 100 mL round bottom flask. The reaction mixture was refluxed at 110-120° C. for 26 hours, following which the Isopropanol was evaporated and the mixture was basified with ammonia in methanol to obtain a slight precipitate. The resulting precipitate was then dissolved in acetone and methanol. To the solution was added silica, and the solvent was removed under reduced pressure to provide a silica gel plug. The plug was transferred on top of a column packed with silica gel, twenty times the weight of plug, eluted with chloroform and 1% methanol in chloroform. Fractions containing the product AAG13 (TLC) were pooled and evaporated to give a solid which was further purified by washing with hexane. The overall yield was 69%. TLC Rf 0.25 (chloroform-methanol 20:1), m.p. 163-164° C., 1H NMR: δ 3.30 (s, 3H, OCH3), 3.66 (s, 3H, N—CH3), 6.55 (s, 2H, NH2, exch), 6.76-7.25 (m, 7H, ArH), 11.65 (s, 1H, 9-NH, exch). Anal. Calculated (C18H16ClN5O. 0.2 CH3(CH2)4—CH3): C, 62.15; H, 5.10; N, 18.87; Cl, 9.55. Found: C, 61.79; H, 4.95; N, 18.72; Cl, 9.48.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14]>>[NH2:14][C:13]1[CH:15]=[CH:16][C:17]([C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:9])=[C:11]([F:10])[CH:12]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1cccc(F)c1
Product: Nc1ccc(C(=O)c2ccccc2)c(F)c1
Temperature: 220 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To stirred 90° C. polyphosphoric acid (150 g) was added 18.32 g (15.0 mmol) of benzoic acid and 8.33 g (7.5 mmol) of 3-fluoroaniline and the bath temperature raised to 220° C. and held there for 1 hour. A solution was obtained at about 130° C. The heating bath was removed and the stirred mixture (sublimate above the solution) was treated cautiously with 60 mL of water. The mixture was stirred at 140°-155° C. for 1 hour, the heating bath removed, 50 mL of 3N HCl added, the mixture poured into 750 mL of water and filtered through a pad of Celite. The filtrate was basified with 15% sodium hydroxide and the resulting solid collected. The 1.88 g of solid was chromatographed on silica gel (methylene chloride) to yield 1.15 g (7%) of white fluffy 4-amino-2-fluorobenzophenone, mp 133°-5° C. 1H NMR (250 MHz, CDCl3): 4.20 (s, 2H, NH2) 6.33-6.50 (m, 2H, aromatic) 7.27-7.55 (m, 4H, aromatic) 7.76-7.79 (m, 2H, aromatic). MS (CI, CH4): 216 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:27][CH2:26][C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]3[O:12][C:13](=[O:15])[CH3:14])[C:6]=2[CH:28]=1.[Br:30]N1C(=O)CCC1=O.N1C2C=CC=CC=2NC=1>O1CCCC1>[Br:30][C:8]1[N:7]([C@@H:10]2[O:27][CH2:26][C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]2[O:12][C:13](=[O:15])[CH3:14])[C:6]2[CH:28]=[C:2]([Cl:1])[C:3]([CH3:29])=[CH:4][C:5]=2[N:9]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1cnc2cc(C)c(Cl)cc21
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc2[nH]cnc2c1
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1c(Br)nc2cc(C)c(Cl)cc21
Yield: 75.9 %

Procedure:
The title compound was prepared according to General Procedure IV using 6-Chloro-5-methyl-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.37 g, 0.87 mmol), 30 ml tetrahydrofuran (Aldrich Sure Seal, Milwaukee), and a total of 1.2 g (7.0 mmol) of N-bromosuccinimide that was added in ca 0.2 equivalents/benzimidazole every 15 min over 1 h. The product from work-up by General Procedure IV was purified on a silica gel column (2.5×20 cm, 230-400 mesh) with dichloromethane containing 0.5% methanol to give 2-Bromo-6-chloro-5-methyl-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.33 g, 0.66 mmol, 75%); MS (ES+): m/z (rel. intensity) 526 (1.0, M+23 (Na)); 1H NMR (DMSO-d6) δ8.18 (s,1H), 7.62 (s, 1H), 5.97-5.904(d, 1H, J=9.4 Hz), 5.78-5.60 (m, 3H), 4.20-4.10 (m, 1H), 4.05-3.97 (m, 1H) 2.41 (s, 3H), 2.25 (s, 3H), 2.04 (s, 3H), 1.78 (s, 3H)
Reaction SMILES: B.CSC.[C:5]1([C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][C:13](O)=[O:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.B(OC)(OC)OC.Cl>O1CCCC1.O>[C:22]1([C:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:13][OH:14])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: B
Agent: COB(OC)OC
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Solvent: O
Product: OCCC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 18 h
Yield: 87.5 %

Procedure:
Borane-methyl sulfide (60 mL, 0.63 mol) was added dropwise to 100 g (0.33 mol) of 3,3,3-triphenylpropanoic acid and 38 mL (0.33 mol) trimethyl borate in 1 liter of anhydrous tetrahydrofuran at room temperature. After 18 hr, the reaction mixture was carefully acidified with 180 mL of conc. hydrochloric acid, stirred for 3 hours and then further diluted with ca. 450 mL of water. The THF layer was collected, the aqueous layer extracted twice with dichloromethane, and the organic layers combined and dried over magnesium sulfate. The organic solution was evaporated to leave a solid, which was recrystallized (two crops) from hexane-dichloromethane to give 83.3 g (87.5%) of the title compound, mp 103°-106° C.
Reaction SMILES: [CH2:1](I)[CH3:2].[CH2:4]([NH:6][S:7]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[N:11]=1)(=[O:9])=[O:8])[CH3:5].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O>[CH2:1]([N:14]1[C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[N:11]=[C:10]1[S:7]([NH:6][CH2:4][CH3:5])(=[O:9])=[O:8])[CH3:2]
Reactant: CCNS(=O)(=O)c1nc2ccccc2[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCNS(=O)(=O)c1nc2ccccc2n1CC
Yield: 74.7 %

Procedure:
46.8 g (0.3 mol) of ethyl iodide are added to a suspension of 67.5 g (0.3 mol) of N-ethyl-1H-benzimidazole-2-sulfonamide and 47.7 g (0.45 mol) of sodium carbonate in 450 ml of acetone and 20 ml of water. The mixture is left under reflux for 20 hours, the acetone is evaporated off, 200 ml of water are added and the product is extracted with methylene chloride. The organic layer is dried (Na2SO4) and evaporated. The residue is recrystallized from an ethanol/water mixture (2:1) to give 56.8 g (75%) of 1,N-diethyl-1H-benzimidazole-2-sulfonamide melting at 135°-9° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@@H:7]2[CH2:11][O:10][CH2:9][C@@H:8]2[NH2:12])=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH3:26][CH:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28].O>C(Cl)Cl>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@@H:7]2[CH2:11][O:10][CH2:9][C@@H:8]2[NH:12][S:29]([CH:27]([CH3:28])[CH3:26])(=[O:31])=[O:30])=[CH:4][CH:3]=1
Reactant: N[C@H]1COC[C@H]1Oc1ccc(Br)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)S(=O)(=O)N[C@H]1COC[C@H]1Oc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of (3S,4S)-4-(4-bromophenoxy)tetrahydrofuran-3-amine (65.6 g, 0.254 mol) in methylene chloride (500 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 53 mL, 0.35 mol). The reaction mixture was cooled to 0° C. and propane-2-sulfonyl chloride (31.2 mL, 0.28 mol) was added drop-wise. The mixture was then stirred at room temperature for 18 hours. The reaction was monitored by proton NMR: additional propane-2-sulfonyl chloride (2.8 mL, 25 mmol) was added and the mixture was stirred at room temperature for an additional 18 hours. Again the reaction was monitored by NMR and additional propane-2-sulfonyl chloride (2.8 mL, 25 mmol) was added. After 2.5 hours the reaction was complete according to NMR analysis. Water (500 mL) was added and the layers were separated. The aqueous layer was extracted with methylene chloride, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in methylene chloride and washed with aqueous hydrochloric acid (1N, 2×300 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford N-[(3S,4S)-4-(4-bromophenoxy)tetrahydrofuran-3-yl]propane-2-sulfonamide as an orange/brown oil. Yield: 92.5 g, 0.254 mol, 100%. 1H NMR (300 MHz, CDCl3) δ 1.36 (d, J=7 Hz, 3H), 1.38 (d, J=7 Hz, 3H), 3.15 (septet, J=7 Hz, 1H), 3.69 (dd, J=8.5, 8.5 Hz, 1H), 3.93 (dd, J=10.6, 1.5 Hz, 1H), 4.10-4.28 (m, 3H), 4.72-4.81 (m, 2H), 6.77 (d, J=9.1 Hz, 2H), 7.41 (d, J=9.1 Hz, 2H). The absolute configuration of this material was established via X-ray crystallographic analysis of a crystal of N-[(3S,4S)-4-(4-bromophenoxy)tetrahydrofuran-3-yl]propane-2-sulfonamide grown from a heptane/ethyl acetate solution. The results are described below.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=[CH:22][CH:21]=4)[C:12]3=[O:30])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.Cl[CH2:33][C:34](Cl)=[O:35].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>ClCCCl>[CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[C:15](=[O:16])[C:14]([CH3:17])([CH3:18])[N:13]([CH2:19][C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=[CH:22][CH:21]=4)[C:12]3=[O:30])=[CH:8][CH:9]=2)[N:4]([C:34](=[O:35])[CH2:33][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH2:3]1
Reactant: CC1(C)CNc2cc(N3C(=O)N(Cc4ccnc5ccccc45)C(C)(C)C3=O)ccc21
Reactant: O=C(Cl)CCl
Reactant: C1COCCN1
Solvent: ClCCCl
Product: CC1(C)CN(C(=O)CN2CCOCC2)c2cc(N3C(=O)N(Cc4ccnc5ccccc45)C(C)(C)C3=O)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 50 mg 3-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-5,5-dimethyl-1-quinolin-4-ylmethyl-imidazolidine-2,4-dione in 1 ml 1,2-dichloroethane 0.04 ml ethyl-diisopropylamine and 13.67 mg chloroacetylchloride were added at 0° C. After stirring for 1 hour at 0° C. 10.5 mg morpholine were added and the reaction mixture was stirred for 1 hour at room temperature. Then 10.5 mg morpholine were added and the mixture was stirred for further 16 hours at room temperature. After removing of the solvent under reduced pressure the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/acetonitrile gradient with 0.1% trifluoroacetic acid). Lyophilization of the solution yielded a white solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:24][CH2:23][CH2:22][CH:21]2[C:25]2[O:29][N:28]=[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH:26]=2)[N:17]=[C:16]([NH:36][C:37]2[CH:41]=[C:40]([CH3:42])[NH:39][N:38]=2)[CH:15]=1.C(N([CH2:48][CH3:49])CC)C>C1COCC1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][C:14]2[N:19]=[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH:21]3[C:25]3[O:29][N:28]=[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH:26]=3)[N:17]=[C:16]([NH:36][CH:37]3[CH:41]=[C:40]([CH3:42])[NH:39][N:38]3[S:7]([C:4]3[CH:5]=[CH:6][C:48]([CH3:49])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH:15]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1cc(Nc2cc(CO)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1=CC(Nc2cc(COS(=O)(=O)c3ccc(C)cc3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)N(S(=O)(=O)c2ccc(C)cc2)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
p-Toluenesulphonyl chloride (3.0 g, 15.7 mmol) was added to a mixture of 6-hydroxymethyl-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 80) (3.13 g, 7.49 mmol), triethylamine (2.5 ml, 18 mmol) in anhydrous THF (50 ml). The resulting mixture was stirred at ambient temperature for 1 hour then heated at reflux for 4 hours. The volatiles were removed by evaporation and the residue dissolved in water and extracted with DCM. The organic extracts were combined and the solvent removed by evaporation. The residue was purification by chromatography on silica gel, eluting with DCM (100%) and then with diethylether (100%) to give the title compound (contaminated with 31% of the 6-chloromethyl derivative) (1.69 g, 31%).
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)#[N:2].C[Si]([N:23]=[N+:24]=[N-:25])(C)C.C([Sn](=O)CCCC)CCC.C1(C)C=CC=CC=1>CO>[N:2]1[NH:23][N:24]=[N:25][C:1]=1[CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([O:10][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:5]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CC[C@H]1CC[C@H](OC(=O)c2ccccc2)CC1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(O[C@H]1CC[C@H](Cc2nn[nH]n2)CC1)c1ccccc1
Temperature: 110 °C

Procedure:
A mixture of trans-benzoic acid 4-cyanomethyl-cyclohexyl ester (3.42 g) obtained in Example (44a), trimethylsilyl azide (3.7 mL), di-n-butyltin oxide (348 mg), and toluene (30 mL) was heated at 110° C. for 48 hours. The progress of the reaction was stopped using methanol, and the reaction mixture was concentrated. The residue was diluted with ethyl acetate, followed by extraction with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was acidified (pH=2) by the addition of 1 N hydrochloric acid, followed by extraction with ethyl acetate (×2). The organic layer was washed with saturated brine, then dried over sodium sulfate, and then concentrated to obtain the title compound (2.57 g, 64%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[CH3:11][C:12]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:13]=1[NH2:14].CC(N(C(C)C)CC)C>O1CCOCC1>[Cl:10][C:4]1[C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=[C:2]([NH:14][C:13]2[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:12]=2[CH3:11])[N:3]=1.[Cl:1][C:2]1[N:3]=[C:4]([NH:14][C:13]2[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:12]=2[CH3:11])[C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)n1
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(Nc2nc(Cl)c(Cl)c(Cl)n2)c(C)c1
Product: Cc1cc(C)c(Nc2nc(Cl)nc(Cl)c2Cl)c(C)c1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
2,4,5,6-tetrachloropyrimidine (0.0134 mol), 1,4-dioxane (30 ml), 2,4,6-trimethyl aniline (0.0134 mol), and N,N-bis(1-methylethyl)ethanamine (0.0136 mol) were added to a flask under argon and stirred at 55° C. for 16 hours. The solvent was evaporated, and the residue was dissolved in CH2Cl2, then purified by column chromatography over silica gel (eluent: CH2Cl2/hexane 1/4, and 1/2). The desired fractions were collected and their solvent was evaporated, yielding 0.15 g 4,5,6-trichloro-N-(2,4,6-trimethylphenyl)-2-pyrimidinamine (interm. 6) and 3.15 g 2,5,6-trichloro-N-(2,4,6-trimethylphenyl)4-pyrimidinamine (interm. 7).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)(Cl)Cl)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH2:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[C:9]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)=[O:20]
Reactant: Clc1ccc(C(Cl)(Cl)c2ccc(Cl)c(Cl)c2)cc1Cl
Reactant: O
Product: O=C(c1ccc(Cl)c(Cl)c1)c1ccc(Cl)c(Cl)c1

Procedure:
reacting said bis(3,4-dichlorophenyl) dichloromethane with water to form 3,3',4,4'-tetrachlorobenzophenone;
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:13]([N:14]2[N+:18]([O-:19])=[C:17]3[CH2:20][CH2:21][CH2:22][CH2:23][C:16]3=[N:15]2)=[CH:12][C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=1.[CH2:24](Br)[C:25]#[CH:26].O>CN(C)C=O>[CH2:26]([N:8]1[C:7]2[CH:12]=[C:13]([N:14]3[N+:18]([O-:19])=[C:17]4[CH2:20][CH2:21][CH2:22][CH2:23][C:16]4=[N:15]3)[C:4]([F:3])=[CH:5][C:6]=2[S:10][C:9]1=[O:11])[C:25]#[CH:24]
Reactant: C#CCBr
Reactant: O=c1[nH]c2cc(-n3nc4c([n+]3[O-])CCCC4)c(F)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCn1c(=O)sc2cc(F)c(-n3nc4c([n+]3[O-])CCCC4)cc21

Procedure:
To a dispersion of sodium hydride (60% oil; 31 mg) in dry N,N-dimethylformamide (3 ml) was added 2-[6fluoro-2(3H)-benzothiazolon-5-yl]-4,5,6,7-tetrahydro-2H-benzotriazole-1-oxide (220 mg) at 0° C., and the resultant mixture was stirred at the same temperature for 30 minutes, followed by addition of propargyl bromide (94 mg). The mixture was allowed to react at 50° to 60° C. for 3 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel thin layer chromatography using a mixture of ethyl acetate and toluene (1:9) as an eluent to give 2-[3-(2-propynyl)-6-fluoro-2(3H)-benzothiazolon-5-yl]-4,5,6,7-tetrahydro-2H-benzotriazole-1-oxide (Compound No. 5; 120 mg). n25.4D 1.5988.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.C(O[C:38]([N:40]([CH2:42][C:43](O)=[O:44])C)=O)(C)(C)C>>[ClH:28].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:7]3[CH:6]=[N:5][C:4]4[C:8]3=[N:9][CH:10]=[N:11][C:3]=4[NH:2][C:43](=[O:44])[CH2:42][NH:40][CH3:38])=[CH:17][CH:16]=2)=[CH:23][C:24]=1[C:29]([F:31])([F:32])[F:30]
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: Cl
Product: CNCC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The titled compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and tert-butoxycarbonyl-sarcosine by using the same method as in Example 96.
Reaction SMILES: [CH:1]1([C:13]([OH:15])=[O:14])[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH:2]1[C:10]([OH:12])=O.C(OC(=O)C)(=O)C>C(O)(=O)C>[CH:1]12[C:13](=[O:14])[O:15][C:10](=[O:12])[CH:2]1[CH2:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][CH2:6]2
Reactant: O=C(O)C1CCC(C(=O)O)C(C(=O)O)C1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)C1CCC2C(=O)OC(=O)C2C1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Into a four-necked flask equipped with a thermometer, a stirrer, a condenser and a heat controller, were charged 100 parts of 1,2,4-cyclohexanetricarboxylic acid, 67 parts of acetic anhydride and 333 parts of glacial acetic acid. The contents were stirred for anhydrization at 120° C. for one hour under heating in a nitrogen gas flow. After cooling to 25° C., the precipitated crystals were separated by filtration and dried in a nitrogen gas flow to obtain a white, solid 1,2,4-cyclohexanetricarboxylic acid-1,2-anhydride.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][S:33]([C:36]3[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=3[F:43])(=[O:35])=[O:34])[C:27]=2[F:44])[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[C:27]([F:44])=[C:28]([NH:32][S:33]([C:36]3[C:37]([F:43])=[CH:38][CH:39]=[CH:40][C:41]=3[F:42])(=[O:35])=[O:34])[CH:29]=[CH:30][CH:31]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCNCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Yield: 114.5 %

Procedure:
To 1,1-dimethylethyl 4-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperazinecarboxylate (1.13 g, 1.694 mmol) in DCM (20 mL) was treated with TFA (20 mL) at rt for 30 min. The reaction mixture was concentrated and the residue was triturated with DCM and hexane to give (1.10 g, 95% yield) of the title compound of Step B. 1H NMR (400 MHz, DMSO-d6) d ppm 10.95 (br. s., 1H), 9.04 (br. s., 1H), 8.34 (d, J=5.5 Hz, 1H), 7.63-7.76 (m, 1H), 7.42-7.49 (m, 1H), 7.38 (t, J=6.1 Hz, 1H), 7.30-7.36 (m, 1H), 7.26 (t, J=9.2 Hz, 2H), 6.52 (d, J=5.4 Hz, 1H), 3.77 (d, J=4.8 Hz, 4H), 3.27 (br. s., 4H). m/z (ES+): 568 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([CH3:17])=[N:11]1.[CH:18](Br)([CH3:20])[CH3:19].[OH-].[Na+].CN(C)C=O>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:18]([CH3:20])[CH3:19])=[CH:4][C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([CH3:17])=[N:11]1
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2Cl)c(C)c1C
Reactant: CC(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(-c2cc(OC(C)C)c(Cl)cc2Cl)c(C)c1C
Temperature: 70 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
A mixture of 1-(2,4-dichloro-5-hydroxyphenyl)-3,4,5-trimethylpyrazole (27.1 g), isopropyl bromide (12.3 g), aqueous sodium hydroxide (4.2 g) and dimethylformamide (150 ml) was stirred at 70° C. for 2 hours. To the reaction mixture, after cooling, were added water and toluene, to form two layers. The toluene layer as separated was washed with water and then dried over anhydrous sodium sulfate. Removal of the toluene by distillation in vacuo gave the titled compound (27.9 g) as a pale yellow oil, which was then purified through silica gel column chromatography to afford a white crystalline solid. m.p. 56°-58° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH:13]([CH2:26][C:27]2[NH:31][CH:30]=[N:29][CH:28]=2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH:13]2[CH2:26][C:27]2[NH:31][CH:30]=[N:29][CH:28]=2)=[CH:23][CH:22]=1)#[N:25]
Reactant: N#Cc1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2Cc2cnc[nH]2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ccc(CN2CCNCC2Cc2cnc[nH]2)cc1

Procedure:
The product from Step 1 (6.17 mmol) was dissolved in absolute ethanol followed by the introduction of 10% Pd/C catalyst then hydrogen under atmospheric pressure. The catalyst was removed via filtration through filter-aid and the product was isolated by removing the solvent under reduced pressure.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[C:24]2[C:19](=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][N:16]=1>C1COCC1>[N+:25]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:19]=1[N:18]=[CH:17][N:16]=[C:15]2[O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc2c(Oc3cccc(C(F)(F)F)c3)ncnc12
Reaction time: 0.25 h
Yield: 57.3 %

Procedure:
To a solution of 3-(trifluoromethyl)phenol (726 mg, 4.48 mmol) in THF (2 mL) was added NaH (179 mg, 4.48 mmol, 60% in mineral oil) at 0° C. and the reaction mixture was stirred for 15 min. Then a solution of 4-chloro-8-nitroquinazoline (Intermediate-7, step 2, 470 mg, 2.24 mmol) in THF (3 mL) was added to the reaction mixture at the same temperature and the reaction mixture was stirred at rt for 4 h. Then the reaction mixture was quenched with 1N HCl at 0° C. and the precipitate obtained was filtered and purified by column chromatography using 5-10% EtOAc in petroleum ether to afford 430 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.88 (s, 1H), 8.68 (d, J=7.8 Hz, 1H), 8.60 (d, J=7.2 Hz, 1H), 7.99-7.94 (t, J=8.4 Hz, 1H), 7.89 (s, 1H), 7.77 (s, 3H); MS (m/z): 336.12 (M+H)+.