Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26](O)=[O:27])[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[NH2:54][CH2:55][CH2:56][C:57]1[C:58]2[CH:65]=[CH:64][CH:63]=[CH:62][C:59]=2[S:60][CH:61]=1.CCN(CC)CC>CN(C=O)C>[S:60]1[CH:61]=[C:57]([CH2:56][CH2:55][NH:54][C:26](=[O:27])[C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]2[CH:1]3[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]2[CH2:4]4)[CH2:8]3)([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[CH3:29])[C:58]2[CH:65]=[CH:64][CH:63]=[CH:62][C:59]1=2
Reactant: NCCc1csc2ccccc12
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)NCCc1csc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.50 g (1.26 mmol) of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan and 0.18 g (1.33 mmol) of 1-hydroxybenzotriazole hydrate in 8 mL of anhydrous DMF (under a N2 atmosphere) was treated in one portion with 0.27 g (1.41 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture was stirred at room temperature for 2 hours, treated with 0.30 g (1.40 mmol) of 3-[2-aminoethyl)benzo[b]thiophene hydrochloride plus 0.25 mL (0.18 g, 1.79 mmol) of Et3N, and stirred for an additional 18 hours. The reaction mixture was partitioned between 100 mL of EtOAc and 150 mL of H2O. The layers were separated and the aqueous layer extracted with fresh EtOAc (3×75 mL). The combined organic layers were washed with 5% aqueous citric acid (3×150 mL), brine (1×150 mL), 5% aqueous NaHCO3 (3×150 mL), and brine again. The organic layer was dried (Na2SO4) and evaporated (vacuum) to an off-white foam. The residue was chromatographed (230-400 mesh SiO2 in a 21×300 mm column, eluted with 2% MeOH in CH2Cl2) to yield the purified product as a white foam, 0.40 g (57%); 1H NMR (CDCl3) δ 1.47-1.92 (17H, m), 2.92 (2H, t, J 7 Hz), 3.25 (1H, d, J 15 Hz), 3.46-3.57 (3H, m), 4.79 (1H, br s), 5.14 (1H, br s), 6.27 (1H, m), 7.02 (2H, m), 7.11-7.86 (8H, m), 8.10 (1H, br s).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:16](=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][C:20]=1[Cl:26]>>[Cl:18][C:19]1[CH:24]=[C:23]([N:13]2[CH2:14][CH2:15][C:16](=[O:17])[N:10]([CH2:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:11][CH2:12]2)[CH:22]=[CH:21][C:20]=1[Cl:26]
Reactant: Clc1ccc(I)cc1Cl
Reactant: O=C1CCNCCN1CCCN1CCCCC1
Product: O=C1CCN(c2ccc(Cl)c(Cl)c2)CCN1CCCN1CCCCC1

Procedure:
The title compound was prepared from 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one (Example 33B) and 1,2-dichloro-4-iodo-benzene in analogy to example 33. MS: 384.4 (MH+, 2Cl).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].Cl.CN.[CH2:16]([N:18](CC)CC)C.O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([S:9]([NH:18][CH3:16])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CNS(=O)(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.8 %

Procedure:
Commercially available 3,4-difluorophenylsulfonylchloride (117 μL, 0.87 mmol) was dissolved in dichloromethane (5 mL), and methylamine hydrochloride (49 mg, 0.73 mmol) and triethylamine (203 μL, 1.45 mmol) were added, followed by stirring at room temperature for 2 hours. To the reaction solution, water (15 mL) was added, extraction was carried out twice with dichloromethane (15 mL), and washing was carried out with saturated brine (15 mL), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, followed by vacuum drying, to afford the desired compound (44.7 mg, yield 30%) as a colorless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)N)=[CH:5][CH:4]=1.[CH3:20][CH:21]([C:27](=O)[CH2:28][CH3:29])[CH2:22][C:23]([O:25]C)=[O:24]>CO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:12]3[C:17](=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:28]([CH3:29])=[C:27]2[CH:21]([CH3:20])[CH2:22][C:23]([OH:25])=[O:24])=[CH:5][CH:4]=1
Reactant: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Reactant: CCC(=O)C(C)CC(=O)OC
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)c(C)c(C(C)CC(=O)O)n2Cc1ccc(Cl)cc1

Procedure:
Following the method of Example 2, but using 1-[(4-chlorophenyl)methyl]-1-(4-methoxyphenyl)-hydrazine hydrochloride and methyl 3-methyl-4-oxohexanoate as the starting materials and methanol as the solvent, the title compound was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][NH2:14])=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:19][C:20]1[CH:21]=[C:22]([NH:28][C:29](=O)[O:30]C2C=CC=CC=2)[CH:23]=[CH:24][C:25]=1[CH2:26][OH:27]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][NH:14][C:29]([NH:28][C:22]3[CH:23]=[CH:24][C:25]([CH2:26][OH:27])=[C:20]([F:19])[CH:21]=3)=[O:30])=[CH:11][C:10]([C:15]([F:16])([F:17])[F:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Reactant: O=C(Nc1ccc(CO)c(F)c1)Oc1ccccc1
Solvent: ClCCl
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Nc1ccc(CO)c(F)c1
Reaction time: 16 h
Yield: 57.2 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (100 mg, 0.316 mmol, 1.0 eq.) in DCM (2.0 mL) was added TEA (0.07 mL, 0.632 mmol, 3.0 eq) followed by phenyl 3-fluoro-4-(hydroxymethyl)phenylcarbamate (82.4 mg, 0.316 mmol, 1.0 eq.) at RT and stirred for 16 h. After completion of the reaction, a solid precipitate was filtered and washed with DCM (2 mL) followed by n-pentane (5 mL) and dried to get 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(hydroxymethyl)phenyl)urea (compound A59) (80 mg; 47%, white solid; TLC system: EtOAc/PE (3:2); Rf: 0.2).
Reaction SMILES: OC1C(=O)C(=O)C=1O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.CC1C(C)(C)[C:28]2[C:23](=[C:24]3C=CC=C[C:25]3=[CH:26][CH:27]=2)[N+:22]=1[CH2:36][CH2:37][CH3:38].C(O)CCC>C1C=CC=CC=1>[N:22]1[C:23]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: CCC[N+]1=C(C)C(C)(C)c2ccc3ccccc3c21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=c1c(O)c(O)c1=O
Solvent: CCCCO
Solvent: c1ccccc1
Product: c1ccc2ncccc2c1
Yield: 89.8 %

Procedure:
A mixture of 0.80 g of 3,4-dihydroxy-3-cyclobutene-1,2-dione, 5.99 g of 2,3,3-trimethyl1-propyl-3H-benzoindolium p-toluenesulfonate obtained in Reference Example 1, 1.64 g of quinoline, 30 ml of butanol and 30 ml of benzene was stirred under reflux for 11 hours. After the reaction solution was concentrated, 30 ml of ethanol was added to the residue, followed by heating for 30 minutes. After cooling, the crystals were filtered off and dried in vacuo to give 2.07 g of Compound 2.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:11]=[C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15]3[N:23]=[CH:24][CH:25]=[CH:26][C:14]=3[N:13]2[C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([C:34]2([NH:38]C(=O)OC(C)(C)C)[CH2:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1.[ClH:46].O1CCOCC1>C(Cl)Cl>[ClH:46].[ClH:46].[ClH:46].[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:11]=[C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15]3[N:23]=[CH:24][CH:25]=[CH:26][C:14]=3[N:13]2[C:27]=1[C:28]1[CH:29]=[CH:30][C:31]([C:34]2([NH2:38])[CH2:37][CH2:36][CH2:35]2)=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4nc5ccccc5s4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3c(-c4nc5ccccc5s4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.4 %

Procedure:
tert-Butyl (1-{4-[2-(1,3-benzothiazol-2-yl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (24.8 mg, 0.0405 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 18 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (21.8 mg, 86.4%) as yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.85-8.65 (m, 3H), 8.16 (dd, J=4.8, 1.6 Hz, 1H), 8.11-8.07 (m, 1H), 7.97 (dd, J=7.8, 1.8 Hz, 1H), 7.83-7.78 (m, 1H), 7.65-7.55 (m, 4H), 7.51-7.46 (m, 1H), 7.45-7.39 (m, 2H), 7.37-7.32 (m, 1H), 7.21-7.15 (m, 1H), 6.98 (dd, J=8.0, 1.6 Hz, 1H), 6.79 (dd, J=8.0, 4.8 Hz, 1H), 2.66-2.54 (m, 4H), 2.28-2.15 (m, 1H), 1.92-1.77 (m, 1H); LCMS: 513 [M+H].
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([OH:10])[CH2:5]1)(=[O:3])[CH3:2].CN(C)C=O.[H-].[Na+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([O:10][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCC(O)C1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCCC(OCc2ccccc2)C1
Reaction time: 0.5 h

Procedure:
1-Acetyl-3-hydroxypiperidine (0.10 mole) is dissolved in 50 ml. of dimethylformamide. 0.12 Mole of sodium hydride (56%) is added over a 10 minute period, and the reaction mixture is stirred for 30 minutes. Benzyl chloride (0.12 mole) is added dropwise over a 30 minute period, and the reaction mixture is then heated on a steam bath for 30 minutes. Water (3 volumes) is added, the solution extracted with ether, the ether extract washed with water and the ether removed by evaporation. A yellow oil is obtained on distillation at 136°-140° C. (0.01 mm Hg.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(Cl)c1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(CBr)c1Cl

Procedure:
2,3-Dichlorotoluene (8.05 g., 0.05 mol.) dissolved in 150 ml. of carbon tetrachloride containing N-bromosuccinimide (8.9 g., 0.05 mol.) was heated to reflux and irradiated with a 275-watt sunlamp for two hours. The mixture was cooled, filtered and evaporated to give α-bromo-2,3-dichlorotoluene. The α-bromo-2,3-dichlorotoluene (2.4 g., 0.01 mol.) and thiourea (0.38 g., 0.005 mol.) were dissolved in 25 ml. of ethanol and refluxed for about sixteen hours. The mixture was cooled, concentrated, treated with ether, filtered and the filter cake recrystallized from water to give carbamimidothioic acid 2,3-dichlorobenzyl ester, m.p. 238°-243° C. (dec.).
Reaction SMILES: SC([OH:4])C.ICC(N([C:17](=[O:31])[CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]1[C@@H:30]2[C@@H:25]([NH:26][C:27]([NH:29]2)=[O:28])[CH2:24][S:23]1)CCCCCCN)=O>>[OH:4][C:17]([CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]1[C@@H:30]2[C@@H:25]([NH:26][C:27]([NH:29]2)=[O:28])[CH2:24][S:23]1)=[O:31]
Reactant: CC(O)S
Reactant: NCCCCCCN(C(=O)CI)C(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21

Procedure:
The mellitin peptide (10 mg) was reduced with mercaptoethanol as described for the 3.2 peptide in Example 1. After rotary evaporation, the sample was resuspended in 2 ml 0.1 M Tris-HCl, 5 mm EDTA, pH 8.0 and reacted with ml dimethylsulfoxide (DMSO), containing 4.3 mg N-iodoacetyl-N-biotinylhexylendiamine (Pierce). This was allowed to react for 15 minutes at room temperature and the biotinylated derivative separated from byproducts on a Sephadex G10 column.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[N:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][C:16](OCC)=[O:17])=[CH:10][CH:9]=1.[OH-].[Na+]>O>[N:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:7]=[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]3[C:16](=[O:17])[CH:15]=2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: Nc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1cc(-c2ccncc2)nc2ccccn12
Temperature: 140 °C
Yield: 16 %

Procedure:
0.406 g (4.31 mmol) of pyridin-2-amine and 1.00 g (5.17 mmol) of ethyl 3-(4-pyridinyl)-3-oxopropionate were added to 3 g of polyphosphoric acid (84% min.). The reaction mixture was heated at 140° C. for 12 hours. After cooling, water was added and the mixture was neutralized with an aqueous solution of sodium hydroxide (30%) and extracted with chloroform. The extracts were washed with a saturated aqueous solution of sodium chloride, dried and evaporated. The residue obtained was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 99/1/0.1 to 85/15/1.5 to give 0.154 g (16%) of the desired compound which was transformed into the oxalate salt in the usual manner to give the pure product as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][N:6]=[CH:5][C:4]=1[Cl:10].[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:10][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:9])[C:3]=1[CH2:2][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: Clc1cncc(Cl)c1CBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2c(Cl)cncc2Cl)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 91.2 %

Procedure:
A mixture of 4-(bromomethyl)-3,5-dichloropyridine (15 g, 62.2 mmol), 4-hydroxybenzaldehyde (7.97 g, 65.4 mmol) and caesium carbonate (22.3 g, 68.5 mmol) in DMF (150 ml) was stirred for 4.5 h at room temperature. The mixture was poured into water and extracted with EtOAc. The organic extract was washed with sodium carbonate solution (×2) and brine, dried (MgSO4) and evaporated in vacuo to give the title compound as a brown solid (16 g). δH (DMSO-d6), 9.91 (1H, s), 8.74 (2H, s), 7.91 (2H, d, J 8.6 Hz), 7.27 (2H, d, J 8.6 Hz), 5.37 (2H, s); m/z (ESI) 282 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([Cl:12])[CH:5]=[CH:4][C:3]=1[OH:13].CCN=C=NCCCN(C)C.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.N1C=CC=CC=1>O>[Cl:12][C:6]1[C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([NH:1][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[C:3]([OH:13])=[CH:4][CH:5]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1c(O)ccc(Cl)c1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1c(O)ccc(Cl)c1C(F)(F)F)c1ccncc1
Temperature: 80 °C
Yield: 50 %

Procedure:
A mixture of 0.75 g of 2-amino-4-chloro-3-trifluoromethylphenol, 0.84 g of WSC, 0.42 g of isonicotinic acid and 5 ml of pyridine was stirred while heating at 80° C. for three hours. To the reaction mixture, 0.1 g of isonicotinic acid was added, and the reaction mixture was stirred while heating for further three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.54 g of N-[3-chloro-6-hydroxy-2-trifluoromethylphenyl]isonicotinamide.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:7]2=1.Cl>CO>[NH2:25][C@@H:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:7]2[C:6]3[C:11](=[C:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[C:10](=[O:12])[N:9]([CH3:13])[C:8]=2[CH:14]=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc21
Agent: Cl
Solvent: CO
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@@H](N)CC(C)C)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.9 %

Procedure:
To a solution of (S)-tert-butyl (1-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (30 mg, 0.068 mmol) in MeOH (3 mL) at 0° C. was added HCl (4N in 1,4-dioxane, 3 mL, 12.00 mmol). The solution was warmed to room temperature and stirred for 2 h. The reaction mixture was then concentrated under reduced pressure and the residue dissolved in ethyl acetate (10 mL). The organic layer was washed with saturated NaHCO3 (2×10 mL) and water (20 mL); dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM-MeOH mixture) to afford (S)-8-((2-amino-4-methylpentyl)oxy)-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (8 mg, 0.021 mmol, 31% yield) as a brown solid. LC/MS, (ESI) m/z 340.2 [(M+H)+, calcd for C20H26N3O2, 340.2]; LC/MS retention time (method B): tR=1.27 min. HPLC retention time (method A): tR=8.30 and HPLC retention time (method B): tR=8.97 min. 1H NMR (400 MHz, CD3OD) δ ppm 8.53 (d, J=5.77 Hz, 1H), 8.33 (d, J=9.54 Hz, 1H), 8.08 (d, J=5.77 Hz, 1H), 7.00-7.06 (m, 2H), 4.21 (m, 1H), 4.02 (m, 1H), 3.73 (s, 3H), 3.47-3.52 (m, 1H), 3.06 (s, 3H), 1.82-1.93 (m, 1H), 1.67-1.76 (m, 2H), 1.26-1.56 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:16][CH:15]3[S:17](=[O:19])(=[O:18])[CH:12]([CH2:13][CH2:14]3)[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:20][Mg]Br.C1(C)C=CC=CC=1.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:11][CH:12]3[S:17](=[O:19])(=[O:18])[CH:15]([CH2:14][CH2:13]3)[CH2:16]2)([OH:9])[CH3:20])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: O=C(c1ccc(Br)cc1)C1CC2CCC(C1)S2(=O)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(O)(c1ccc(Br)cc1)C1CC2CCC(C1)S2(=O)=O
Reaction time: 0.5 h

Procedure:
To a solution of (4-bromo-phenyl)-(8,8-dioxo-8-thia-bicyclo[3.2.1]oct-3-yl)-methanone (885 mg, 2.58 mmol) in THF (7 ml) at −10° C. to −8° C. was added methylmagnesium bromide 1.4M in toluene/THF 3/1 (3.68 ml, 5.16 mmol). The reaction mixture was stirred for 30 min. The solution was cooled with an ice bath and quenched with a solution of aqueous saturated NH4Cl and water 1/1 (7.5 ml), diluted and extracted with ethyl acetate. The organic phases were combined, washed with brine, dried using Na2SO4, filtered and concentrated in vacuo. The crude product (940 mg, 2.54 mmol, 97%) was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26](O)=[O:27])=[CH:22][N:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1>O.CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]([N:63]4[CH2:68][CH2:67][O:66][CH2:65][CH2:64]4)=[O:27])=[CH:22][N:21]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)N2CCOCC2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.6 %

Procedure:
A mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoic acid (0.40 g), 1-hydroxybenzotriazole monohydrate (0.17 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.22 g), morpholine (0.10 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 4-((2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoyl)morpholine as yellow crystals (0.41 g, yield 91%). Recrystallization from ethyl acetate-hexane gave yellow prism crystals. melting point: 180-181° C.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[NH:21][N:22]=[C:23]([C:24]([OH:26])=[O:25])[C:13]=3[N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:27](=O)([O-])O.[Na+]>CO>[C:5]1([C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[NH:21][N:22]=[C:23]([C:24]([O:26][CH3:27])=[O:25])[C:13]=3[N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)c1n[nH]c2c1nc(-c1ccccc1)c1ccccc12
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1n[nH]c2c1nc(-c1ccccc1)c1ccccc12
Reaction time: 0.5 h

Procedure:
18 μL of thionyl chloride were initially introduced into 0.5 ml of methanol and the mixture was stirred for 30 min. 19 mg of 5-phenyl-1H-pyrazolo[4,3-c]isoquinoline-3-carboxylic acid (60) in 0.5 ml of methanol were then added dropwise. The mixture was stirred at RT for 12 h, after which a saturated solution of sodium hydrogen carbonate was added and the whole was extracted, in each case 1×, with ethyl acetate and methylene chloride. The organic phases were combined, dried over magnesium sulfate and concentrated under reduced pressure and the residue was purified by means of HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The following was obtained: 61.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][C:8]2[S:9][C:10]3[N:11]=[CH:12][N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][C:8]2[S:9][C:10]3[N:11]=[CH:12][N:13]=[C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:33](=[O:34])[CH2:32][O:31][C:30]5[CH:36]=[CH:37][C:27]([O:26][CH3:25])=[CH:28][CH:29]=5)[CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(OCC(=O)O)cc1
Reactant: Fc1ccc(CCc2nc3c(N4CCNCC4)ncnc3s2)cc1
Product: COc1ccc(OCC(=O)N2CCN(c3ncnc4sc(CCc5ccc(F)cc5)nc34)CC2)cc1
Yield: 39 %

Procedure:
This compound was prepared from 2-(4-fluorophenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidine using 4-methoxyphenoxyacetic acid in a yield of 39%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:7][N:6]=[C:5]([NH:8][C:9]([NH:11][S:12]([C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[O:10])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](I)[CH3:32].C(O)(=O)C>CC(C)=O.C(#N)C>[CH2:31]([N:7]1[C:3]([S:2][CH3:1])=[N:4][C:5]([NH:8][C:9]([NH:11][S:12]([C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[O:10])=[N:6]1)[CH3:32]
Reactant: CCI
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1n[nH]c(SC)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: CC#N
Product: CCn1nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OC)nc1SC
Temperature: 0 °C
Reaction time: 72 h

Procedure:
To a stirred mixture of 1.0 gram (0.0027 mole) of methyl 2-[(5-methylthio-1H-1,2,4-triazol-3-yl)aminocarbonyl]aminosulfonylbenzoate and 0.7 grams of potassium carbonate in 30 ml of acetone at room temperature, 0.8 ml of ethyl iodine was added by way of syringe and the resulting white suspension stirred 3 days. The mixture was poured into 250 ml of ice water and acidified to pH 3-4 with glacial acetic acid. The aqueous acidic mixture was extracted with 1:1 mixture of ethyl ether/ethyl acetate and the extract washed with brine, dried (MgSO4), and evaporated to yield a white solid residue which was suspended in acetonitrile and filtered, yield 0.3 grams, m.p. 188°-191°.