Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][NH:5][C:4](=[O:7])[CH:3]=1.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[F:17])[CH:12]=O.[C:18]1(=O)[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH2:19]1>>[Br:8][C:9]1[CH:10]=[C:11]([CH:12]2[C:19]3[C:20](=[O:24])[CH2:21][CH2:22][CH2:23][C:18]=3[NH:1][C:2]3[NH:6][NH:5][C:4](=[O:7])[C:3]2=3)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: Nc1cc(=O)[nH][nH]1
Reactant: O=C1CCCC(=O)C1
Product: O=C1CCCC2=C1C(c1ccc(F)c(Br)c1)c1c([nH][nH]c1=O)N2
Yield: 24.7 %

Procedure:
5-Amino-1,2-dihydropyrazol-3-one (0.15 g, 1.5 mmol), 3-bromo-4-fluorobenzaldehyde (0.3 g, 1.5 mmol), and 1,3-cyclohexanedione (0.17 g, 1.5 mmol) were processed as described in Example 2 to provide 0.14 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 1.85 (m, 2H), 2.18 (m, 2H), 2.55 (m, 2H), 4.94 (s,1H), 7.12 (m, 1H), 718 (t, 1H), 7.4 (dd, 1H), 9.75 (s, 1H), 10.35 (bs, 1H), 11.33 (bs, 1H); MS (ESI−) m/z 376 (M−H)−; Anal. Calcd for C16H13N3BrFO2: C, 50.79; H, 3.44; N, 11.11. Found: C, 50.45; H, 3.42; N, 11.33.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[O:11][C:10]2=[O:20])[CH:5]=[CH:4][N:3]=1.[CH2:21]([O:23][C:24](=[O:29])[CH2:25][N:26]=[C:27]=[O:28])[CH3:22]>N1C=CC=CC=1>[CH2:21]([O:23][C:24](=[O:29])[CH2:25][NH:26][C:27]([NH:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[O:11][C:10]2=[O:20])[CH:5]=[CH:4][N:3]=1)=[O:28])[CH3:22]
Reactant: CCOC(=O)CN=C=O
Reactant: Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Solvent: c1ccncc1
Product: CCOC(=O)CNC(=O)Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1-(2-amino-pyridin-4-ylmethyl)-1H-benzo[d][1,3]oxazine-2,4-dione (600 mg, see preparation 7b) in pyridine (7 ml) was added isocyanato-acetic acid ethyl ester (0.4 ml). The reaction mixture was stirred at room temperature for 3 hours, and the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried (MgSO4) and evaporated under reduced pressure. The resulting oil was treated with EtOAc (3 ml) and gave a precipitate that was isolated by filtration and dried in vacuo, affording {3-[4-(2,4-Dioxo-4H-benzo[d][1,3]oxazin-1-ylmethyl)-pyridin-2-yl]-ureido}-acetic acid ethyl ester (0.53 g). Step 2: This anhydride intermediate was converted into the title compound by reaction with O-(4-cyanobenzyl)hydroxylamine hydrochloride (see preparation 10), using general procedure 1A. 13C-NMR (DMSO-d6) δ 170.3, 167.4, 154.8, 153.5, 151.4, 148.5, 146.7, 141.8, 132.7, 132.2, 129.1, 128.0, 118.6, 115.4, 114.8, 112.9, 111.5, 110.7, 109.3, 76.0, 60.3, 45.2, 41.2, 14.0.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:23]([CH:24]=[O:25])[CH2:22][CH2:21][C:20]([C:26]([O:28]C)=[O:27])=[CH:19][C:18]=3[CH:30]=2)=[CH:10][CH:9]=1)[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:23]([CH:24]=[O:25])[CH2:22][CH2:21][C:20]([C:26]([OH:28])=[O:27])=[CH:19][C:18]=3[CH:30]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-[4-(3-ethoxypropoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.31 g). To the solution was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at 50° C. for 1.5 hours and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-(3-ethoxypropoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.3 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH:14]2[CH2:17]C[CH2:15]2)[C:5]([C:6](OCC)=[O:7])=[CH:4][N:3]=1.O.[NH2:19][NH2:20]>C(O)C>[Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH:14]([CH3:17])[CH3:15])[C:5]([C:6]([NH:19][NH2:20])=[O:7])=[CH:4][N:3]=1
Reactant: NN
Reactant: CCOC(=O)c1cnc(Cl)cc1NC1CCC1
Solvent: CCO
Solvent: O
Product: CC(C)Nc1cc(Cl)ncc1C(=O)NN
Temperature: 80 °C

Procedure:
To a stirred solution of ethyl 6-chloro-4-(isopropylamino)nicotinate (2) (3 g, 12.39 mmol) in ethanol (10 mL), hydrazine hydrate (3 mL) was added and refluxed at 80° C. for 3 h. The reaction mixture was cooled and concentrated to obtain crude compound. The residue obtained was triturated with diethyl ether and hexane and filtered to get solid, 6-chloro-4-(isopropylamino)nicotinohydrazide (10). LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 0.58 min; LCMS (ES-API), m/z 229.6 (M+H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:22])[C:5]2[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][C:14]3[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][CH:15]=3)[NH:8][C:6]=2[N:7]=1.CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.Cl.[CH2:42]([O:44][C:45](=[O:55])[C@H:46]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[NH2:47])[CH3:43]>CN(C=O)C>[CH2:42]([O:44][C:45](=[O:55])[C@@H:46]([NH:47][C:19]([C:17]1[S:18][C:14]([CH2:13][CH2:12][CH2:11][C:9]2[NH:8][C:6]3[N:7]=[C:2]([NH2:1])[NH:3][C:4](=[O:22])[C:5]=3[CH:10]=2)=[CH:15][CH:16]=1)=[O:21])[CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH3:43]
Reactant: Nc1nc2[nH]c(CCCc3ccc(C(=O)O)s3)cc2c(=O)[nH]1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCCc2cc3c(=O)[nH]c(N)nc3[nH]2)s1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
To a solution of 9 (254 mg, 0.8 mmol) in anhydrous DMF (10 mL) was added N-methylmorpholine (145 mg, 1.44 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (253 g, 1.44 mmol). The resulting mixture was stirred at room temperature for 2 h. To this mixture were added N-methylmorpholine (145 mg, 1.44 mmol) and L-glutamate diethyl ester hydrochloride (290 mg, 1.2 mmol). The reaction mixture was stirred for an additional 4 h at room temperature and then evaporated to dryness under reduced pressure. The residue was dissolved in the minimum amount of CHCl3/MeOH (4:1) and chromatographed on a silica gel column (2×15 cm) and with 5% CHCl3 in MeOH as the eluent. Fractions that showed the desired spot (TLC) were pooled and the solvent evaporated to dryness to afford 252 mg of 10 as yellow powder in 63% yield. 1H NMR (DMSO-d6): δ 1.14-1.21 (m, 6H), 1.81-2.05 (m, 4H), 2.32-2.39 (t, J=7.6 Hz, 2H), 2.49-2.52 (t, J=7.2 Hz, 2H), 2.78-2.81 (t, J=7.2 Hz, 2H), 4.02-4.07 (m, 4H), 4.30-4.35 (m, 1H), 5.88 (s, 1H), 5.94 (s, 2H), 6.89-6.90 (d, J=3.6 Hz, 1H), 7.68-7.69 (d, J=3.6 Hz, 1H), 8.61-8.63 (d, J=8 Hz, 1H), 10.71 (s, 1H), 11.19 (s, 1H).
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].OO.C([O-])([O-])=[O:19].[Na+].[Na+]>CC(O)=O>[CH:1]([S:4]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1)=[O:19])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(SC(C)C)cc1
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(S(=O)C(C)C)cc1
Yield: 65 %

Procedure:
A solution of ethyl 4-isopropylsulfanylbenzoate (350 mg, 1.6 mmol) and H2O2 (180 μL of 30% w/v, 1.6 mmol) in AcOH (2 mL) was stirred at ambient temperature for 3 h. The mixture was poured into sat. aq. Na2CO3 and the pH was adjusted to 10 with solid Na2CO3. The mixture was extracted with EtOAc (3×). The organics were combined and washed with sat. aq. Na2CO3, water (2×), then brine. The organic layer was dried over magnesium sulfate and was evaporated to dryness. The residue was purified by column chromatography (20-50% EtOAc in hexanes) to give ethyl 4-isopropylsulfinylbenzoate (65%). ESI-MS m/z calc. 240.1. found 241.3 (M+1)+. Retention time: 1.16 minutes (3 min run).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:19]>C(Cl)(Cl)Cl>[O:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:18](=[O:19])[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:5][CH2:6]1
Reactant: CCCCCCCCCCCCCCCCOC(=O)Cl
Reactant: NCCN1CCOCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCOC(=O)NCCN1CCOCC1
Temperature: 25 °C

Procedure:
8.6 Grams of N-(2-aminoethyl)morpholine, 7.2 g of triethylamine and 120 ml of chloroform were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and stirred with ice cooling. To the resulting solution was slowly added dropwise 18.2 g of hexadecyl chloroformate. After completion of the addition, the temperature of the solution was returned to room temperature, followed by refluxing with heating for 0.5 hour. The reaction mixture was cooled to room temperature, washed with water, dried over anhydrous magnesium sulfate and, then, concentrated under reduced pressure. The residue was recrystallized from acetonitrile to obtain 21.1 g of the desired product. m.p. 65° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])CCC.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][N:31]([CH3:33])[CH3:32])=[CH:19][CH:18]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][N:31]([CH3:33])[CH3:32])([OH:34])[C:5]2[C:4]([C:3]([NH:2][CH3:1])=[O:10])=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:19][CH:18]=1
Reactant: CN(C)Cc1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: CNC(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1C(O)(c1ccc(Cl)cc1)c1ccccc1CN(C)C
Temperature: 5 °C

Procedure:
To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube maintained under a nitrogen atmosphere there is added at room temperature 19.7 g (0.146 mole) of N-methyl benzamide and 400 ml. dry tetrahydrofuran. The reaction flask is immersed in an ice bath and cooled to an internal temperature of 5°C. Stirring is initiated and 204 ml. of 1.6 M. n-butyl lithium (~0.321 mole) in hexane is added dropwise over about 1 hour maintaining the temperature below 8°C. The resulting dilithio salt is stirred at 5°C. for an additional hour and then a solution of 40 g. (0.146 mole) of 4'-chloro-2-dimethylaminomethyl benzophenone in 500 ml. tetrahydrofuran is added dropwise over about 1 hour maintaining the temperature between -10 to 10°C. The resulting mixture is stirred at 5°C. for 1 hour longer and 150 ml. of saturated ammonium chloride is added maintaining the temperature at about 10°C. The layers are separated and the organic phase dried over ahydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is crystallized from ether to give α-(4-chlorophenyl)-α-(2-dimethylaminomethyl phenyl)-α-hydroxy-N-methyl-o-toluamide; m.p. 154°-156°C.
Reaction SMILES: [NH:1]([C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[C@H:2]([C:19]([NH:21][C@H:22]([C:40]([N:42]1[CH2:81][CH2:80][CH2:79][C@H:43]1[C:44]([NH:46][C@H:47]([C:49]([NH:51][C@H:52]([C:69]([O:71]CC1C=CC=CC=1)=[O:70])[CH2:53][CH2:54][CH2:55][CH2:56][NH:57][C:58]([O:60][CH2:61][C:62]1[CH:68]=[CH:67][CH:66]=[CH:65][C:63]=1[Cl:64])=[O:59])=[O:50])[CH3:48])=[O:45])=[O:41])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:39])[NH:28][S:29]([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[Cl:14])=[O:9].[OH-].[Na+].C(Cl)(Cl)Cl.CO>CO>[NH:1]([C:82]([O:84][C:85]([CH3:86])([CH3:88])[CH3:87])=[O:83])[C@H:2]([C:19]([NH:21][C@H:22]([C:40]([N:42]1[CH2:81][CH2:80][CH2:79][C@H:43]1[C:44]([NH:46][C@H:47]([C:49]([NH:51][C@H:52]([C:69]([OH:71])=[O:70])[CH2:53][CH2:54][CH2:55][CH2:56][NH:57][C:58]([O:60][CH2:61][C:62]1[CH:68]=[CH:67][CH:66]=[CH:65][C:63]=1[Cl:64])=[O:59])=[O:50])[CH3:48])=[O:45])=[O:41])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:39])[NH:28][S:29]([C:32]1[CH:33]=[CH:34][C:35]([CH3:36])=[CH:37][CH:38]=1)(=[O:31])=[O:30])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[Cl:14])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCCCNC(=O)OCc2ccccc2Cl)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCCCNC(=O)OCc2ccccc2Cl)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
At 0° C. to the solution of 250 mg (0196 mmol) of Boc-Lys(ClZ)-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 15) in 6 ml of methanol 5 ml of the solution of NaOH in methanol (2 mol/L) were added. The reaction mixture was stirred at 0° C. for 2 h and TLC (chloroform/methanol, 15:1) indicated complete disappearance of Boc-Lys(ClZ)-Arg(Tos)-Pro-Ala-Lys(ClZ)-Obzl (SEQ ID NO: 15). The reaction mixture was neutralized to pH 7 and evaporated at room temperature to remove methanol. The residue was acidified to pH 1–2 with hydrochloric acid (2 mol/L) to provide 200 mg (86%) of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C(N(CC)CC)C.[C:32](Cl)(Cl)=[S:33].[NH2:36][CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:32]([NH:36][CH2:37][CH2:38][N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[S:33])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: NCCN1CCCC1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3cc(C)c(NC(=S)NCCN4CCCC4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 10.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (51 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (51 mg) was then added to the solution, and the mixture was stirred at room temperature for 6 hr. Next, 1-(2-aminoethyl)pyrrolidine (50 mg) was added thereto, and the mixture was further stirred at room temperature for 16 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (8 mg, yield 10%).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[O:19]C(=O)C)[C:8]([N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15])=[O:9])(=O)C.N>C(O)C.O>[OH:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[OH:19])[C:8]([N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15])=[O:9]
Reactant: CC(=O)Oc1ccc(C(=O)N2CCNC2=O)cc1OC(C)=O
Agent: N
Solvent: O
Solvent: CCO
Product: O=C1NCCN1C(=O)c1ccc(O)c(O)c1
Reaction time: 0.25 h
Yield: 78.4 %

Procedure:
1-[3,4-Bis(acetyloxy)benzoyl]-2-imidazolidinone (11 g, 0.035 mol) was suspended in a mixture of 50 ml of ethanol and 50 ml of water, 4.2 ml (0.07 mol) of aqueous ammonia solution was added with stirring. After 15 minutes, a clear solution was formed, which was evaporated to a small volume. 1-(3,4-Dihydroxybenzoyl)-2-imidazolidinone crystallized out yielding 6.1 g of the title compound, melting point 208°-210° C.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:20][NH:21][CH:22]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23]1>>[ClH:19].[CH3:20][N:21]([CH:22]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23]1)[S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: CNC1CCN(C)C1
Product: CCc1cc(-c2ccc(S(=O)(=O)N(C)C3CCN(C)C3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 90 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with methyl(1-methylpyrrolidin-3-yl)amine as described in Steps 5 and 6, Example 24 to give the title compound as a yellow solid (90% yield). LC/MS: RT 2.12 min; m/e 396; 1H NMR (δ, ppm): 11.82 (1H, br), 7.61 (1H, d), 7.37 (1H, s), 7.22 (1H, d), 4.08 (1H, m), 2.76 (3H, s), 2.20-2.69 (m), 1.94 (1H, m), 1.55 (1H, m), 1.10 (3H, t).
Reaction SMILES: Cl.[CH3:2][NH:3][CH:4]([CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([NH:16][CH3:17])=[O:15])=[CH:8][CH:7]=1.C(N(CC)CC)C.Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH3:2][N:3]([CH:4]([CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([NH:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29]
Reactant: CNC(=O)COc1ccc(CC(C)NC)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)COc1ccc(CC(C)N(C)CC(=O)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
N-methyl-2-(4-methylaminocarbonylmethoxyphenyl)-1-methylethanamine hydrochloride (2.73 g) was suspended in tetrahydrofuran (10 ml) containing triethylamine (6 ml) and a solution of α-bromoacetophenone (1.99 g) in tetrahydrofuran (10 ml) was added dropwise. After stirring overnight this solution was treated with saturated sodium carbonate solution, extracted with dichloromethane, the organic phase was dried (magnesium sulphate), filtered and evaporated to give a red oil which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:9][C@@H:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:11]([NH:13][CH2:14][C:15]#[N:16])=[O:12])=[CH:4][CH:3]=1.[CH3:27][S:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.[I-].[K+].[C:40](=O)([O-])[O-:41].[K+].[K+]>C1(OC)C=CC=CC=1>[C:15]([CH2:14][NH:13][C:11](=[O:12])[C@@H:10]([O:9][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:40](=[O:41])[C:32]2[CH:33]=[CH:34][C:29]([S:28][CH3:27])=[CH:30][CH:31]=2)=[CH:3][CH:4]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:17][CH:18]([CH3:20])[CH3:19])#[N:16]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(Br)cc1)C(=O)NCC#N
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: COc1ccccc1
Product: CSc1ccc(C(=O)c2ccc([C@H](O[C@@H](CC(C)C)C(=O)NCC#N)c3ccccc3)cc2)cc1
Temperature: 90 °C

Procedure:
(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide from example 68 (150 mg, 0.361 mmol), 4-(methylthio)phenyl boronic acid (67 mg, 0.398 mmol, 1.1 eg), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (II)complex) (7.9 mg, 0.011 mmol, 0.03 eg), potassium iodide (180 mg, 1.08 mmol, 3 eg), potassium carbonate (149 mg, 1.08 mmol, 3 eg) were mixed together in anisole (5 mL). The reaction mixture was degased 3× with nitrogen, then heated at 90° C. under latm of CO for 18 hours. The crude reaction mixture was concentrated under high vacuum and the residue was chromatographed with 30% EtOAc/hexane to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([O:13]CC)=[O:12].[OH-].[K+]>C1COCC1.C(O)C.O>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1sc2nccnc2c1N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(C(=O)O)sc2nccnc12
Yield: 98.2 %

Procedure:
A solution of ethyl 7-aminothieno[2,3-b]pyrazine-6-carboxylate 7 (10 g, 44.8 mmol) and potassium hydroxide (5.0 g, 90 mmol) in THF (50 mL), ethanol (50 mL) and water (20 mL) was stirred at 70° C. for 2 h. Quenched in a cold solution of 2N HCl, and the resulting precipitate was collected to give crude 7-aminothieno[2,3-b]pyrazine-6-carboxylic acid 8 (8.59 g, 98%). 1H-NMR (400 MHz, DMSO-d6) 7.03 (br s, 2H), 8.77 (s, 2H), 12.8 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH:25]1(C2C=C(N)NN=2)C[CH2:26]1>>[CH:1]1([C:2]2[CH:24]=[C:5]3[N:6]=[C:7]([C:16]4[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=4)[C:8]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[CH:9][N:4]3[N:3]=2)[CH2:26][CH2:25]1
Reactant: Cc1cc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Reactant: Nc1cc(C2CC2)n[nH]1
Product: O=Cc1ccc(-c2nc3cc(C4CC4)nn3cc2-c2ccccc2)cc1

Procedure:
This compound was prepared in a manner according to 4-(2-methyl-6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzaldehyde by using 3-cyclopropyl-1H-pyrazol-5 amine in the first step.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31].C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: NCCCO
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NCCCO)c(Cl)c32)c(F)cc1F
Temperature: 45 °C
Reaction time: 43 h
Yield: 46.7 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg), 3-amino-1-propanol (75 mg) and triethylamine (200 mg) were added to pyridine (350 mg), and the mixture was stirred at 45° C. for 43 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Concentrated hydrochloric acid (120 mg) was added to the residue, and the mixture was concentrated under reduced pressure. Ethanol (1 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (80 mg) as a colorless powder.