Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC([N:8]=[C:9]=[O:10])=CC=1[N:11]=[C:12]=[O:13].C1C([NH2:20])=CC=C(S(C2C=CC(N)=CC=2)(=O)=O)C=1.[C:31]1([OH:37])C=CC=C[CH:32]=1>CCC(C)=O.C(N(CC)CC)C>[NH2:20][C:12]([NH2:11])=[O:13].[NH2:8][C:9]([O:37][CH2:31][CH3:32])=[O:10]
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Reactant: Oc1ccccc1
Reactant: Nc1ccc(S(=O)(=O)c2ccc(N)cc2)cc1
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(N)=O
Product: NC(N)=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 542 %

Procedure:
To 31.5 g of 2,4-toluene diisocyanate was added dropwise a solution of 21.5 g of 4,4′-diaminodiphenyl sulfone in 60 mL of MEK at 70° C. with stirring at 300 to 500 rpm over a period of 4 hours, and the reaction was carried out for another 4 hours to obtain a white viscous slurry reaction mixture. Then, the reaction mixture was cooled to 50° C., and 17.1 g of phenol was poured into the reaction mixture to be dissolved therein, after which 0.015 g of triethylamine was added thereto as a catalyst, and the reaction was carried out for 4 hours to obtain a yellow, transparent and viscous reaction mixture. This reaction mixture was freed of the solvent and concentrated under reduced pressure to be solidified, after which the resulting solid was ground and then dried overnight in a vacuum to obtain about 70 g of a urea-urethane composition as light-yellow powder.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]2[NH:29][N:30]=[C:31]([C:32](O)=[O:33])[C:25]=2[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH:10]1[CH2:11][CH2:12][N:13]([C:32]([C:31]2[C:25]3[CH2:24][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:28][CH2:27][C:26]=3[NH:29][N:30]=2)=[O:33])[CH2:14][CH2:15]1
Reactant: Fc1ccc(Cl)c(C2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)O)c2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)N3CCC(c4cc(F)ccc4Cl)CC3)c2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.2 %

Procedure:
To a solution of 4-(2-chloro-5-fluorophenyl)piperidine hydrochloride (17, 70 mg, 0.28 mmol), 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (89 mg, 0.34 mmol), and diisopropylethylamine (0.15 mL, 0.84 mmol) in DMF (5.4 mL) was added EDCI (64 mg, 0.34 mmol) and HOBt (45 mg, 0.34 mmol). The resulting solution was stirred at ambient temperature for 24 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (4×20 mL). The combined organic extracts were washed with a saturated brine solution (8×20 mL), H2O (20 mL), and concentrated to dryness under reduced pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 100% EtOAc in hexanes) to give tert-butyl 3-(4-(2-chloro-5-fluorophenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (49) as a white solid (78 mg, 60%): 1H NMR (300 MHz, DMSO-d6) δ 12.96 (s, 1H), 7.48 (dd, J=8.7, 5.4 Hz, 1H), 7.34-7.21 (m, 1H), 7.16-7.06 (m, 1H), 5.28-5.11 (m, 1H), 4.77-4.57 (m, 1H), 4.53-4.38 (m, 2H), 3.66-3.52 (m, 2H), 3.30-3.04 (m, 2H, overlaps with H2O), 2.92-2.61 (m, 3H), 1.92-1.74 (m, 2H), 1.69-1.49 (m, 2H), 1.41 (s, 9H); ESI MS m/z 462 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].Cl.O1CCOC[CH2:17]1>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: O=C(O)c1cc(O)cc(C(F)(F)F)c1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxy-5-(trifluoromethyl)benzoic acid (3.56 g, 17.3 mmol) in methanol (110 mL) was added 4.0M hydrogen chloride in dioxane (110 mL, 460 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was concentrated. The residue was purified by flash chromatography on a silica gel column to give the desired product as white solid.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.ClC(Cl)(O[C:10](=[O:16])OC(Cl)(Cl)Cl)Cl.C(N(CC)C(C)C)(C)C.[Br:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]([C:38](=[O:40])[CH3:39])[C@@H:33]([CH3:41])[CH2:32][NH:31]2>ClCCCl.O>[C:38]([N:34]1[C:35]2[C:30](=[CH:29][C:28]([Br:27])=[CH:37][CH:36]=2)[N:31]([C:10]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[O:16])[CH2:32][C@@H:33]1[CH3:41])(=[O:40])[CH3:39]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCC1CC1
Reactant: CC(=O)N1c2ccc(Br)cc2NC[C@@H]1C
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)N1c2ccc(Br)cc2N(C(=O)OCC2CC2)C[C@@H]1C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A 250-mL round-bottom flask was charged with cyclopropylmethanol (1.90 g, 26.3 mmol), triphosgene (1.50 g, 5.28 mmol), N,N-diisopropylethylamine (4.0 mL, 23 mmol) and 1,2-dichloroethane (100 mL). The resulting solution was stirred for 1 h at 50° C. 1-[(2S)-6-Bromo-2-methyl-1,2,3,4-tetrahydroquinoxalin-1-yl]ethan-1-one (710 mg, 2.64 mmol) and N,N-diisopropylethylamine (4.0 mL, 23 mmol) in 1,2-dichloroethane (20 mL) were added, and the resulting solution stirred overnight at 50° C. After cooling to room temperature, the reaction mixture was poured into water (30 mL). The aqueous layer was separated and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via column chromatography on silica gel (eluting with 1:12, ethyl acetate/petroleum ether) to afford cyclopropylmethyl (3S)-4-acetyl-7-bromo-3-methyl-1,2,3,4-tetrahydroquinoxaline-1-carboxylate in (850 mg, 88%) as a yellow solid. MS (ESI, pos. ion) m/z 367, 369 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:25])[C@H:6]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31]Cl.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31][O:1][CH2:2][CH2:3][NH:4][C:5](=[O:25])[C@H:6]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: COCCOCCl
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)NCCO)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOCCNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-benzyloxycarbonyl-L-phenylalanine-N-(2-hydroxylethyl)amide (7.0 g, 20.4 mmol) in dry dichloromethane (150 ml) under an argon atmosphere was added 2-methoxyethoxymethyl chloride (5.6 ml, 49.0 mmol) and diisopropylethylamine (10.7 ml, 61.4 mmol). The reaction mixture was stirred overnight at room temperature, after which time starting material was still detectable by TLC. The solvent volume was concentrated to one third, an equal volume of DMF was added and the reaction mixture was stirred for a further 60 hours at room temperature. The solvents were removed under reduced pressure, the residue was dissolved in ethyl acetateand washed successively with 1M hydrochloric acid, sat. aq. sodium hydrogencarbonate and brine. The organic phase was dried over sodium sulphate, filtered and concentrated to afford the desired product as a pale yellow oil which crystallised when left under high vacuum for ca. 1 hour. Yield: 8.0 g (90%). 1H--NMR; δ(CDCI3), 7.33-7.14 (10H, m), 6.84 (1H, br s), 5.89 (1H, br s), 5.01 (2H, m), 4.54 (2H, s), 4.46 (1H, m), 3.56-3.26 (11H, m), 3.02 (2H, m).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11](Cl)=[N:12][CH:13]=2)[N:8]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[CH2:23][CH2:22][CH2:21]3)[CH:7]=1)=O)C.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1.C([N:43](CC)CC)C>CN1C(=O)CCC1>[CH2:23]1[C:24]2[C:20](=[CH:19][C:18]([N:8]3[C:9]4[C:14](=[CH:13][N:12]=[C:11]([NH:40][C:37]5[CH:38]=[CH:39][C:34]([N:31]6[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]6)=[CH:35][CH:36]=5)[CH:10]=4)[C:15](=[O:16])[C:6]([C:4]([NH2:43])=[O:3])=[CH:7]3)=[CH:26][CH:25]=2)[CH2:21][CH2:22]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2cc(Cl)ncc2c1=O
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc(Nc3cc4c(cn3)c(=O)c(C(N)=O)cn4-c3ccc4c(c3)CCC4)cc2)CC1
Temperature: 200 °C

Procedure:
To a solution of 7-chloro-1-indan-5-yl-4-oxo-1,4-dihydro-[1,6]naphthyridine-3-carboxylic acid ethyl ester (40 mg, 0.11 mmol) and 4-(4-Methyl-piperazin-1-yl)-phenylamine (45 mg, 0.23 mmol) in 1 mL of NMP was added triethylamine (24 mg, 0.24 mmol). The reaction was heated in a microwave reactor at 200° C. for 2 hours. The solvent was evaporated under vacuo and the product was purified by preparative HPLC (32 mL/min, 5-100% H2O/MeCN (0.01% TFA, v/v) gradient over 15 min). The title compound was obtained as a yellow solid (6.9 mg, 10%). 1H NMR (400 MHz, CD3OD) δ (ppm): 9.11 (s, 1H), 8.57 (s, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.35 (m, 3H), 7.25 (dd, J=1.9 Hz, J=7.9 Hz, 1H), 6.96 (d, J=8.8 Hz, 2H), 6.13 (s, 1H), 3.40-3.80 (br, 8H), 3.01 (m, 4H), 2.96 (s, 3H), 2.17 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H30N6O2: 495.24 (M+H), Found: 495.1.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:32][CH:31]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]3[N:47]=[CH:48][N:49]=[C:23]23)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O.C(OCC)(=O)C>[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]4[NH:3][C:4](=[O:7])[O:5][N:43]=4)=[CH:32][CH:31]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]3[N:47]=[CH:48][N:49]=[C:23]23)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(Cc3ccccc3)CC2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCN(Cc3ccccc3)CC2)c2ncnn12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
A mixture of hydroxylammonium chloride (1.44 g), sodium hydrogen carbonate (2.32 g) and dimethyl sulfoxide (15 mL) was stirred at 50° C. for 30 min, a solution of 4′-{[4-(1-benzylpiperidin-4-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (749 mg) in dimethyl sulfoxide (3 mL) was added, and the mixture was stirred at 90° C. for 17 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (269 mg) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=50/50→10/90 (volume ratio)], and crystallized from a mixture of ethyl acetate and diisopropyl ether to give the title compound as colorless crystals (133 mg, 16%).
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:14]3[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH3:22])[C:13]=3[CH2:12][CH:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]=2[CH2:9]1)C1C=CC=CC=1.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.[Cl:45]C(OC(Cl)=O)C>ClCCCl>[ClH:45].[CH3:22][O:21][C:20]1[C:13]2[CH2:12][CH:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]3[CH2:9][NH:8][CH2:16][C:15]=3[C:14]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: COc1cccc2c1CC(c1ccccc1)C1=C2CN(Cc2ccccc2)C1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCCl
Product: COc1cccc2c1CC(c1ccccc1)C1=C2CNC1
Product: Cl

Procedure:
To a solution of 0.89 g (2.52 mmol) of 2-benzyl-6-methoxy-4-phenyl-2,3,4,5-tetrahydrobenzo[e]isoindole, from Step 6, in 22 mL of 1,2-dichloroethane is added 0.11 g (0.05 mmol) of 1,8-bis(dimethylamino)-naphthalene and 0.33 mL (3.15 mmol) of 1-chloroethylchloroformate at 0° C. The solution is heated to reflux for 2 h and the solvent removed in vacuo. The residue is filtered through silica gel, eluting with 25% ethyl acetate in hexanes. After concentration under reduced pressure, methanol (20 mL) is added and the solution is heated to reflux for 30 minutes, before the solvent is removed in vacuo to give the title compound.
Reaction SMILES: [F:1][CH:2]([F:40])[O:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH2:29][N:30]2[CH2:35][CH2:34][CH:33]([C:36]([F:39])([F:38])[F:37])[CH2:32][CH2:31]2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].C(N(CC)CC)C.Cl.[NH2:49][OH:50].O>CO>[F:40][CH:2]([F:1])[O:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=3)=[N:16][C:15]=2[CH2:29][N:30]2[CH2:31][CH2:32][CH:33]([C:36]([F:39])([F:38])[F:37])[CH2:34][CH2:35]2)[CH:9]=[CH:8][C:5]=1[C:6]([NH:49][OH:50])=[NH:7]
Reactant: N#Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCC(C(F)(F)F)CC2)cc1OC(F)F
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: N=C(NO)c1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCC(C(F)(F)F)CC2)cc1OC(F)F
Temperature: 140 °C
Yield: 54.8 %

Procedure:
To a solution of 830 mg of 2-difluoromethoxy-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-benzonitrile in 13 mL of methanol was added 5.7 mL of triethylamine followed by 430 mg of hydroxylamine hydrochloride. The resulting mixture was heated in a sealed tube to 140° C. under microwave irradiation for 30 minutes. After allowing it to cool down to room temperature, the mixture was poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from heptane 100 to heptane 60/ethyl acetate 40) to give 480 mg of 2-difluoromethoxy-N-hydroxy-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-benzamidine.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](OCC)(=[O:25])[CH2:21][C:22]([CH3:24])=O.C(O)(=O)C>O>[C:1]1([N:7]2[C:11](=[O:12])[C:10]3[C:22]([CH3:24])=[CH:21][C:20](=[O:25])[N:13]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:9]=3[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C1CC(Nc2ccccc2)=NN1c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(=O)n(-c2ccccc2)c2[nH]n(-c3ccccc3)c(=O)c12
Yield: 34.5 %

Procedure:
1-Phenyl-3-anilino-2-pyrazolin-5-one (25 g), ethyl acetoacetate (18 g) and acetic acid (150 ml) were refluxed with heating for 6 hours. The reaction solution was diluted while water, and the resulting solid was crystallized from acetonitrile to obtain 10.9 g of 2,7-diphenyl-4-methylpyrazolo(3,4-b)pyridine-3,6-dione. Melting point 145°-147° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.CN(C)C=O.[H-].[Na+].Cl[CH:14]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:15]1[CH:16]=[CH:17][C:18]2[N:22]=[N:21][N:20]([CH3:23])[C:19]=2[CH:24]=1>O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:14]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[C:15]2[CH:16]=[CH:17][C:18]3[N:22]=[N:21][N:20]([CH3:23])[C:19]=3[CH:24]=2)=[CH:26][CH:27]=1
Reactant: Cn1nnc2ccc(C(Cl)c3ccc(Cl)cc3)cc21
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nnc2ccc(C(c3ccc(Cl)cc3)n3cncn3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
To a stirred solution of 28.4 parts of 1H-1,2,4-triazole in 135 parts of N,N-dimethylformamide were added 11.4 parts of a sodium hydride dispersion 80% under nitrogen atmosphere. After stirring for 1 hour at room temperature, a solution of 40 parts of 6-[chloro(4-chlorophenyl)methyl]-1-methyl-1H-benzotriazole in 90 parts of N,N-dimethylformamide was added to the mixture. The whole was stirred for 1 hour at 60° C. The reaction mixture was diluted with 50 parts of water and the whole was evaporated. The residue was extracted with ethyl acetate. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 1,1'-oxybisethane. The product was filtered off and dried, yielding 13 parts (29.2%) of 6-[(4-chlorophenyl)-(1H-1,2,4-triazol-1-yl)methyl]-1-methyl-1H-benzotriazole; mp. 178.9° C. (compound 64).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:19](=[O:21])[CH3:20])[C:10]([O:14][CH2:15][CH:16]=[CH:17]C)=[CH:11][CH:12]=2)[O:7][C:6](=[O:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH:28]=O.[CH2:37](O)C>O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:19](=[O:21])[CH:20]=[CH:28][C:27]3[CH:26]=[C:25]([O:24][CH3:23])[C:32]([O:33][CH3:34])=[C:31]([O:35][CH3:36])[CH:30]=3)[C:10]([O:14][CH2:15][C:16]([CH3:17])=[CH2:37])=[CH:11][CH:12]=2)[O:7][C:6](=[O:22])[CH:5]=1
Reactant: CC=CCOc1ccc2c(C)cc(=O)oc2c1C(C)=O
Reactant: CCO
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=C(C)COc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-methylallyloxy-8-acetylcoumarin (2.04 g, 0.0075 mol) and 3,4,5-trimethoxy-benzaldehyde (1.47 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified. The precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 1.7 g of product m.p. 128-130° C., 1H-NMR (CDCl3) δ: 1.74 (s, 3H); 2.43 (s, 3H); 3.75-3.88 (m, 9H); 4.55 (s, 2H); 4.98 (d, 2H, J=15 Hz); 6,16 (s, 1H); 6.72 (s, 1H); 6.93 (d, 1H, J=8.9 Hz); 6.94 (d, 1H, J=16 Hz); 7.23 (d, 1H, J=16 Hz); 7.61 (d, 1H, J=8.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].C([Li])CCC.[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([S:23](F)(=[O:25])=[O:24])[N:17]=1>C(COC)OC>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH:4][S:23]([C:18]1[N:17]=[C:16]([CH3:15])[CH:21]=[C:20]([CH3:22])[N:19]=1)(=[O:24])=[O:25]
Reactant: Cc1cc(C)nc(S(=O)(=O)F)n1
Reactant: Nc1c(Cl)cccc1Cl
Agent: [Li]CCCC
Solvent: COCCOC
Product: Cc1cc(C)nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2,6-dichloroaniline (1.0 g, 6.2 mmol) in dimethoxyethane (25 mL) was added butyl lithium (3.9 mL, 6.24 mmol). After 15 minutes, the solution was cooled to -30° and 4,6-dimethyl-2-pyrimidinesulfonyl fluoride (1.18 g, 6.2 mmol) was added. The mixture stirred for 12 hours with warming to 25° C. The mixture was concentrated and the residue was treated with 1N NaOH (2 mL) and extracted with ethyl acetate. The aqueous layer was acidified with 1N HCl and a solid was collected, m.p. 261°-263° C. NMR (90 MHZ) D6 -Acetone: δ 7.5 (m, 4H) and 2.5 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].O.[N+:11]([CH:14]([CH:17]=O)[CH:15]=[O:16])([O-:13])=[O:12].[Na].C(O)(=O)/C(=C(\C=O)/Br)/Br>Cl.O>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([NH:1][CH:17]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=[O:16])[CH:9]=[CH:8][CH:7]=1
Reactant: Nc1cccc(CO)c1
Reactant: O=CC(C=O)[N+](=O)[O-]
Agent: Cl
Agent: O=C/C(Br)=C(/Br)C(=O)O
Agent: [Na]
Solvent: O
Product: O=CC(=CNc1cccc(CO)c1)[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
3-Aminobenzyl alcohol (4.97 g, 0.0404 mol) was dissolved in 4 mL conc HCl. Sodium nitromalonaldehyde monohydrate (prepared from mucobromic acid according to the procedure in Organic Syntheses Vol IV, pp 844, 1963) (4.25 g, 0.0269 mol) was dissolved in 35 mL water and added to the amine solution (a yellow precipitate formed immediately)—a further 80 mL of water being added to aid stirring. After 10 min, the precipitate was filtered, washed with water and air dried overnight to give the product (4.3 g) as a yellow solid.
Reaction SMILES: Br[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH3:10])([CH3:9])[CH2:4][C:3]1=O.[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C.O.C(=O)(O)[O-].[Na+]>[NH2:15][C:13]1[S:14][C:2]2[C:7](=[O:8])[CH2:6][C:5]([CH3:10])([CH3:9])[CH2:4][C:3]=2[N:12]=1
Reactant: CC1(C)CC(=O)C(Br)C(=O)C1
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)CC(=O)c2sc(N)nc2C1
Yield: 83.7 %

Procedure:
28 g of 2-bromo-5,5-dimethylcyclohexane-1,3-dione and 11.7 g of thiourea are dissolved in 200 ml of ethanol. After the weakly exothermic reaction has subsided, the mixture is refluxed for a further 6 hours. The solution is diluted with 400 ml of water and neutralised with saturated sodium bicarbonate solution. The precipitated crystals are collected by filtration and dried in vacuo at 80° C., affording 21 g of 2-amino-5,5-dimethyl-7-oxo-4,5-dihydro-6H-benzthiazole with a melting point of 203°-205° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:6]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=2)[CH:7]=1.[Cl:32][C:33]1[N:38]=[C:37](Cl)[C:36]([CH3:40])=[CH:35][N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:28]([O:27][C:25]([NH:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:35]2[C:36]([CH3:40])=[CH:37][N:38]=[C:33]([Cl:32])[N:34]=2)=[CH:7][C:6]=1[CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCc2cc(N)ccc2NC(=O)OC(C)(C)C)c1
Reactant: Cc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cnc(Cl)nc1Nc1ccc(NC(=O)OC(C)(C)C)c(CCc2cccc(NC(=O)OC(C)(C)C)c2)c1
Yield: 50.1 %

Procedure:
To a solution of tert-butyl [3-(2-{5-amino-2-[(tert-butoxycarbonyl)amino]phenyl}ethyl)phenyl]carbamate (0.4 g, 0.9 mmol) (prepared in Example C52, step C) and 2,4-dichloro-5-methylpyrimidine (0.152 g, 0.936 mmol) in N,N-dimethylformamide (7 mL) was added potassium carbonate (0.662 g, 4.79 mmol). The resultant mixture was stirred overnight at rt overnight. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and then dried (Na2SO4), filtered and concentrated to give the residue, which was purified by silica gel column chromatography to give the desired product (0.25 g, 39%). LCMS for C29H37ClN5O4 (M+H)+: m/z=554.2.