Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=2)[CH2:28][CH2:27]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:37]([C:36]3[CH:35]=[CH:34][C:33]([CH2:32][N:29]4[CH2:30][CH2:31][O:26][CH2:27][CH2:28]4)=[CH:40][CH:39]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccc(F)cc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(CN6CCOCC6)cc5)nc34)CC2)cc1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-4-(4-(4-fluorobenzyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.12 g, 0.30 mmol) and EtOH (5 mL), 4-(morpholinomethyl)benzaldehyde (0.068, 0.33 mmol) in EtOH (1.8 mL) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.9 mL, 0.9 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and purified by column chromatography on a Biotage SP1 system eluting with methanol (2-10%) in dichloromethane. The title compound was isolated as a pale yellow solid after trituration with diethyl ether (0.013 g, 7.6%); 1H-NMR (500 Mz, DMSO-d6): δ 2.38 (m, 4H), 2.60 (m, 4H), 3.54 (s, 2H, NCH2), 3.56 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.66 (m, 4H), 7.17 (d, J=8.5 Hz, 2H, ArH, C6H4—F), 7.40 (br dd, J=8.5, 6.0 Hz, 2H, ArH, C6H4—F), 7.47 (d, J=8.0 Hz, 2H, ArH), 8.14 (d, J=8.0 Hz, 2H, ArH), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.33 min—565/567 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 565.1725, calculated for C28H31BrFN6O (M+H)+: 565.1727.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[NH:13][C:12](=[O:14])[CH2:11][N:10]1[CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1>ClCCl>[NH:18]1[CH2:17][CH2:16][CH:15]([N:10]2[CH2:11][C:12](=[O:14])[NH:13][C:9]2=[O:8])[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC(=O)NC2=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN(C2CCNCC2)C(=O)N1
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (0.300 mL) was added to a solution of tert-butyl 4-(2,4-dioxoimidazolidin-1-yl)piperidine-1-carboxylate (32 mg, 0.113 mmol) in dichloromethane (1 mL). After 4 h, the reaction was concentrated to give the title compound. MS: m/z=184.04 (M+1).
Reaction SMILES: CC1C(CCC(O)=O)=C(CC2NC(/C=C3/C(C=C)=C(C)C(N/3)=O)=C(C)C=2CCC(O)=O)NC=1/C=C1/C(C)=C(C=C)C(N/1)=O.[Fe-3:44]([C:55]#[N:56])([C:53]#[N:54])([C:51]#[N:52])([C:49]#[N:50])([C:47]#[N:48])[C:45]#[N:46].[K+:57].[K+].[K+]>>[Fe-4:44]([C:53]#[N:54])([C:49]#[N:50])([C:45]#[N:46])([C:47]#[N:48])([C:51]#[N:52])[C:55]#[N:56].[K+:57].[K+:57].[K+:57].[K+:57]
Reactant: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: C=CC1=C(C)/C(=C/c2[nH]c(Cc3[nH]c(/C=C4\NC(=O)C(C)=C4C=C)c(C)c3CCC(=O)O)c(CCC(=O)O)c2C)NC1=O
Agent: [K+]
Product: N#C[Fe-4](C#N)(C#N)(C#N)(C#N)C#N

Procedure:
Namely, in the measurement solution vessel 8, an analyte sample was caused to be acted on with bilirubin oxidase in the presence of potassium ferricyanide to produce potassium ferrocyanide. A solution under measurement containing potassium ferrocyanide from the measurement solution vessel 8 and a buffer fluid from the buffer fluid vessel 9 were introduced into the solution inlet pipe 13 to be mixed together and then injected into the electrolysis cell 1 by the solution injection mechanism 12 so that electrochemical measurement was done.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=2[CH:21]([CH3:23])[CH3:22])=[CH:8][N:7]=[C:6](S(C)(=O)=O)[N:5]=1)[CH3:2].[NH4+:28].[OH-]>C(COC)OC>[CH2:1]([NH:3][C:4]1[C:9]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=2[CH:21]([CH3:23])[CH3:22])=[CH:8][N:7]=[C:6]([NH2:28])[N:5]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCNc1nc(S(C)(=O)=O)ncc1Cc1cc(OC)c(OC)cc1C(C)C
Agent: [OH-]
Solvent: COCCOC
Product: CCNc1nc(N)ncc1Cc1cc(OC)c(OC)cc1C(C)C
Temperature: 145 °C
Yield: 47 %

Procedure:
To ethyl-[5-(2-isopropyl-4,5-dimethoxy-benzyl)-2-methanesulfonyl-pyrimidin-4-yl]-amine (0.078 g, 0.2 mmol) in microwave reactor vial was added 2.0 mL dimethoxy ethane and 0.5 mL concentrated NH4OH. The vial was capped and placed in a microwave reactor. The internal temperature was warmed to 145° C. After 2 hours an additional portion of 0.4 mL concentrated NH4OH was added and the mixture was heated an additional 2 hours. The mixture was cooled and concentrated in vacuo. Purification via flash chromatography (96:4 CH2Cl2/MeOH) afforded N*4*-ethyl-5-(2-isopropyl-4,5-dimethoxy-benzyl)-pyrimidine-2,4-diamine (0.031 g, 47%) as a pale yellow solid; Mass Spec M+H=329. Use of different alkyllithium reagents in step 1 and/or different substituted amines in steps 6 and 8 of the above procedure afforded additional compounds under the same or very similar reaction conditions. Additional compounds made by the procedure of Example 3 are shown in Table 1.
Reaction SMILES: C([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)(O)=O.CNC1CCN(CC2C=CC=CC=2)CC1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C)C=O>[NH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14]
Reactant: O=C1CCc2cc(C(=O)O)ccc2N1
Agent: CCOP(=O)(C#N)OCC
Agent: CNC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCc2ccccc2N1
Temperature: 0 °C

Procedure:
3 Grams of 6-carboxy-3,4-dihydrocarbostyril and 3.5 g of 4-methylamino-1-benzylpiperidine were dispersed in 40 ml of dimethylformamide, to this dispersion was added dropwise, under ice-cooled condition, 2.61 ml of diethyl cyanophosphate and 2.39 ml of triethylamine in 10 ml of dimethylformamide solution. The reaction mixture was stirred under ice-cooled condition for 1 hour, further stirred at room temperature for 2 hours, then the reaction mixture was poured into ice-water. Said mixture was extracted with chloroform, then extract was dried with anhydrous sodium carbonate, then the solvent was removed by evaporation. The residue thus obtained was purified by means of a silica gel column chromatography, and recrystallized from acetonitrile to yield 3 g of [N-methyl-N-(1-benzyl-4-piperidyl)amino]carbonyl]-3,4-dihydrocarbostyril.1/2-hydrate. White powdery substance. Melting point: 186°-188° C. (decomp.).
Reaction SMILES: I.I[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[C:12]([CH3:24])[CH:11]=2)[C:4]=1[NH2:25].[CH2:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:27]#[CH:28]>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:25][C:4]1[C:3]([C:28]#[C:27][CH2:26][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[N:8][CH:7]=[N:6][C:5]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[C:12]([CH3:24])[CH:11]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc(I)c3N)cc2C)cn1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2ccc(Nc3ncnc(C#CCNC(=O)OC(C)(C)C)c3N)cc2C)cn1
Yield: 73.8 %

Procedure:
6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine hydroiodide (500 mg) was dissolved in a mixed solvent of acetonitrile (14.8 mL)/triethylamine (11.0 mL), and tert-butyl 2-propynylcarbamate (166 mg), trans-dichlorobis(triphenylphosphine)palladium(II) (31.3 mg) and copper(I) iodide (10.2 mg) were sequentially added. The title compound (303 mg) was obtained as a powder by the reaction in the same manner as in Example 9 (iv).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][C:15](=[O:21])[NH:16]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH2:24]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][C:15](=[O:21])[NH:16]3)[CH2:2][CH2:3]1)[CH3:23]
Reactant: O=C1CCc2c(cccc2OCCCN2CCNCC2)N1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CCOc1ccccc1N1CCN(CCCOc2cccc3c2CCC(=O)N3)CC1

Procedure:
2.9 Grams of 5-(3-piperazinylpropoxy)-3,4-dihydrocarbostyril, 2.5 g of o-bromoethoxybenzene and 1.5 g of sodium carbonate are mixed with 80 ml of n-butanol and refluxed for 20 hours. After cooling, the reaction mixture is concentrated under reduced pressure and the residue is extracted with chloroform. Then chloroform is removed by distillation and the residue thus obtained is recrystallized from ethanol to obtain 2.2 g of 5-{3-[4-(2-ethoxyphenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril in the form of colorless needle-like crystals having a melting point of 155°-156° C.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[CH:12][C:13]([N+:15]([O-])=O)=[CH:14][C:6]1=2.I.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](SC)=[NH:26]>C(O)C.ClCCl.[Pd]>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[CH:12][C:13]([NH:15][C:25]([C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)=[NH:26])=[CH:14][C:6]1=2
Reactant: CSC(=N)c1cccs1
Reactant: CN(C)CCN1CCSc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: I
Solvent: ClCCl
Solvent: CCO
Product: CN(C)CCN1CCSc2ccc(NC(=N)c3cccs3)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.6 %

Procedure:
A suspension of N,N-dimethyl-2-(6-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethanamine (75 mg, 0.281 mmol) and palladium, 10 wt. % on activated carbon (29.9 mg, 0.028 mmol) in ethanol (5 mL) was stirred at room temperature under an atmosphere of hydrogen (balloon pressure) for 90 minutes. During this time, the yellow color of the reaction dissipated. To this mixture was then added methyl thiophene-2-carbimidothioate hydroiodide (160 mg, 0.561 mmol), and the resulting suspension was stirred overnight at room temperature. The mixture was then diluted with dichloromethane and filtered to remove palladium. The organic filtrate was further diluted with water and saturated sodium carbonate (1:1). The organic layer was separated, and the aqueous layer was extracted again with dichloromethane. The combined organics were dried, filtered, concentrated, and then chromatographed in 1:19 (2M NH3 in methanol):ethyl acetate, giving the desired product 27 (61 mg, 62.8%). 1H NMR (DMSO-d6) δ 7.71 (d, J=3.3 Hz, 1H), 7.58 (d, J=5.1 Hz, 1H), 7.10-7.06 (m, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.37 (brs, 2H), 6.17 (s, 1H), 6.08 (d, J=7.8 Hz, 1H), 3.63-3.58 (m, 2H), 3.39-3.32 (m, 2H), 3.01-2.96 (m, 2H), 2.42 (t, J=6.9 Hz, 2H), 2.10 (s, 6H); ESI-MS (m/z, %): 347 (MH+, 100), 276 (74); ESI-HRMS calculated for C17H23N4S2 (MH+), calculated: 347.1358, observed: 347.1349; HPLC purity: 95% by area.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15](C)[CH2:16]C#N)=[CH:11][CH:10]=1.Cl.[C:21]([OH:24])(=[O:23])[CH3:22]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:16])[CH2:22][C:21]([OH:24])=[O:23])=[CH:11][CH:10]=1
Reactant: CC(=O)O
Reactant: CC(CC#N)c1ccc(-c2ccc(F)cc2F)cc1
Agent: Cl
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
1 g. of 3-(2',4'-difluoro-4-biphenylyl)butyronitrile and 6 ml. of acetic acid and 6ml. of concentrated hydrochloric acid are heated under reflux for 2 hours under nitrogen. The mixture is evaporated. The residue is dissolved in dilute NaOH and the solution is washed with ether and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].CCN(CC)CC.C(N(CC(O)=O)CC(O)=O)CN(CC([O-])=O)CC([O-])=O.O.O.[Na+].[Na+].Cl[C:44](=[CH2:47])[C:45]#[N:46].S(=O)(=O)(O)O>CO>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:45]([NH2:46])=[CH:44][CH:47]=[N:11]1
Reactant: C=C(Cl)C#N
Reactant: NNc1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])CN(CCN(CC(=O)O)CC(=O)O)CC(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ccnn1-c1ccc(F)cc1F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A 250 mL RBF containing a solution of 1-(2,4-difluorophenyl)hydrazine hydrochloride (10.33 g, 57 mmol), Et3N (8.0 mL, 57 mmol), EDTA disodium salt dihydrate (50 mg, 0.13 mmol) in 100 mL of MeOH was fitted with a reflux condenser, and heated to 70° C. To the refluxing solution was added 2-chloroacrylonitrile (5.0 mL, 57 mmol) slowly. The solution was heated at reflux for an additional 7.5 h. It was cooled to RT then concentrate sulfuric acid (5.2 mL, 97 mmol) was added slowly and the reaction mixture again heated to reflux for 18 h. The reaction mixture was cooled to 0° C. and treated with Na2CO3 monohydrate (21.00 g) and stirred at RT for 8 h. The reaction mixture was concentrated on the rotovap to remove the MeOH. The resulting rust colored solid was then treated with 100 mL of water and extracted with EtOAc (2×100 mL). The combined EtOAc layers were washed with brine, dried and concentrated. Purification of the crude material on an ISCO 120 g column (20-80% EtOAc in hexanes) afforded 1-(2,4-difluorophenyl)-1H-pyrazol-5-amine as an orange-brown viscous oil. MS (ES+): 196.1 (M+H)+. A further general description of this procedure can be found in U.S. Pat. No. 4,803,215.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Br:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CS(C)=O.[OH:40][CH2:41][C@@H:42]1[CH2:46][C@@H:45]([OH:47])[CH2:44][NH:43]1>C(OCC)(=O)C>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:43]3[CH2:44][C@H:45]([OH:47])[CH2:46][C@H:42]3[CH2:41][OH:40])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Br:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OC[C@@H]1C[C@@H](O)CN1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccccc1Br
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H](O)C[C@H]2CO)cc1-c1ccccc1Br
Temperature: 130 °C
Reaction time: 24 h
Yield: 47.6 %

Procedure:
A mixture of 800 mg (1.38 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-N-methyl-isobutyramide, 4 ml dimethyl sulfoxide and 1.15 g (6.9 mmol) (2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine was stirred at 130° C. for 24 h. The reaction mixture was cooled to room temperature, diluted with 100 ml ethyl acetate and washed with 200 ml 1 N sodium carbonate solution and 100 ml water. The combined aqueous layers were extracted twice with 100 ml ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated. Purification by flash chromatography gave 434 mg (48%) of the title compound as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.[CH2:14]([N:16]([CH2:20][CH3:21])[C:17](Cl)=[O:18])[CH3:15].O>N1C=CC=CC=1>[CH2:14]([N:16]([CH2:20][CH3:21])[C:17](=[O:18])[O:13][C:3]1[C:2]([Cl:1])=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:12])=[CH:5][CH:4]=1)[CH3:15]
Reactant: CCN(CC)C(=O)Cl
Reactant: O=C1NCCc2ccc(O)c(Cl)c21
Solvent: O
Solvent: c1ccncc1
Product: CCN(CC)C(=O)Oc1ccc2c(c1Cl)C(=O)NCC2
Temperature: 100 °C
Reaction time: 5 h
Yield: 91.5 %

Procedure:
A mixture of 8-chloro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (1e, 5.6 g, 28 mmol), and diethylcarbamic chloride (4.3 g, 31 mmol) in pyridine (100 mL) was stirred at 100° C. for 5 hours. To the reaction mixture was added H2O (300 mL). The mixture was extracted with EtOAc (2×200 mL). The combined organic layers were washed with 1 N HCl (2×300 mL) and brine (300 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (EtOAc) to give 8-chloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl diethylcarbamate (1f, 7.6 g, 90%) as brown oil.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][CH2:7][CH3:8])[CH2:3][CH2:2]1.CS(O[CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25]#[C:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)=[CH:29][N:28]=3)=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)(=O)=O>CN(C=O)C>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([C:30]2[CH:31]=[CH:32][C:27]([C:26]#[C:25][C:21]3[CH:20]=[C:19]4[C:24](=[CH:23][CH:22]=3)[N:16]([CH2:15][CH2:14][N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH2:6][CH2:7][CH3:8])[CH:17]=[CH:18]4)=[N:28][CH:29]=2)=[CH:38][CH:37]=1
Reactant: CCCNCC1CC1
Reactant: CS(=O)(=O)OCCn1ccc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc21
Solvent: CN(C)C=O
Product: CCCN(CCn1ccc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc21)CC1CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
63 μL (0.44 mmol) cyclopropylmethyl-propyl-amine are added to a solution of 100 mg (0.22 mmol) 2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethyl methanesulphonate in 2 mL DMF and the reaction mixture is stirred for 16 h at 60° C. The mixture is evaporated down i. vac., the residue is taken up in DCM, the organic phase is washed with water and dilute K2CO3 solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified twice by chromatography (Alox, cyc/EtOAc 8:2 and cyc/DCM 1:1).
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][CH2:8][N:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:10]([NH:12][C:13]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22])=[O:14])=[S:11].C(N(CC)CC)C>ClCCl>[C:25]1([N:9]2[CH2:8][CH2:7][S:11][C:10]2=[N:12][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[C:21]([F:24])([F:23])[F:22])=[O:14])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(NC(=S)N(CCO)c1ccccc1)c1cnccc1C(F)(F)F
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N=C1SCCN1c1ccccc1)c1cnccc1C(F)(F)F
Temperature: 20 °C
Reaction time: 3 h
Yield: 45.6 %

Procedure:
Methanesulfonyl chloride (0.14 ml) was added to an ice-cooled solution of 1-(2-hydroxyethyl)-1-phenyl-3-(4-trifluoromethyl-3-pyridylcarbonyl)thiourea (0.60 g) and triethylamine (0.42 ml) in dichloromethane, and stirred for 3 hours at 20° C. The mixture was washed (water), dried (magnesium sulfate), evaporated and the residue recrystallized (ethanol) to give 3-phenyl-2-(4-trifluoromethyl-3-pyridylcarbonyl)iminothiazolidine (0.26 g, Compound D-60).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH:29]([O:42][C:43]([NH:45][C:46]1[NH:47][C:48](=[O:59])[C:49]2[N:50]=[CH:51][N:52]([CH2:55][C:56](O)=[O:57])[C:53]=2[N:54]=1)=[O:44])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:56](=[O:57])[CH2:55][N:52]1[CH:51]=[N:50][C:49]2[C:48](=[O:59])[NH:47][C:46]([NH:45][C:43]([O:42][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:44])=[N:54][C:53]1=2)[CH3:2]
Reactant: O=C(O)Cn1cnc2c(=O)[nH]c(NC(=O)OC(c3ccccc3)c3ccccc3)nc21
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1)C(=O)Cn1cnc2c(=O)[nH]c(NC(=O)OC(c3ccccc3)c3ccccc3)nc21

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(4-chloro-2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with [2-N-(benzhydryloxycarbonyl)-guanin-9-yl]-acetic acid as per the procedure of example 13. 1H NMR (400 MHz; DMSO-d6) δ 11.65 (brs, 1H), 11.25 (s, 0.45H), 11.23 (s, 0.55H), 9.20 (brs, 1H), 8.39 (s, 1H), 8.03–7.91 (m, 2H), 7.82 (s, 0.55H), 7.80 (s, 0.45H), 7.46 (d, 4H), 7.38 (t, 4H), 7.30 (dt, 2H), 6.87 (s, 1H), 5.15 (s, 1.1H), 4.96 (s, 0.9H), 4.47 (s, 0.9H), 4.22 (q, 0.9H), 4.10 (s, 1.1H), 4.09 (q, 1.1H), 3.69 (t, 1.1H), 3.52 (t, 0.9H), 3.45 (t, 1.1H), 3.29 (t, 0.9H), 1.26 (t, 1.35H), 1.16 (t, 1.65H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[C:19](Cl)(=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23]>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:19](=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: CCCCC(=O)Cl
Product: CCCCC(=O)Nc1nc2c(OC)ccc(N3CCOCC3)c2s1

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and valeroyl chloride the title compound was obtained as a light yellow solid (48%), MS: m/e=350 (M+H+).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[N+:7]([C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][C:16](O)=[O:17])=[C:12]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)[CH:11]=1)([O-:9])=[O:8].C(Cl)Cl.[OH-].[Na+]>>[N+:7]([C:10]1[CH:20]=[CH:19][C:13]2[O:14][CH2:15][C:16](=[O:17])[C:25]3[N:21]([CH:22]=[CH:23][CH:24]=3)[C:12]=2[CH:11]=1)([O-:9])=[O:8]
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1-n1cccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1COc2ccc([N+](=O)[O-])cc2-n2cccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
PCl5 (1.30 g, 6.25 mmol) was added slowly to (4-Nitro-2-pyrrol-1-yl-phenoxy)-acetic acid (1.5 g, 5.7 m mol) in CH2Cl2 (40 mL, 0.6 mol) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was poured onto crushed ice, basified with 1 N NaOH, and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. LCMS 245.10 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH:14]1([N:20]=[C:21]=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C)C=O>[CH:14]1([NH:20][C:21](=[O:22])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C=NC1CCCCC1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)NC2CCCCC2)n1

Procedure:
Following a procedure similar to that described in Preparation 1. the desired compound was prepared from 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 4.7 g of cyclohexyl isocyanate and 30 ml of dimethylformamide. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8]C(C)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH4+].[Br-].[C:13]([OH:16])(=[O:15])[CH3:14]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:14]([C:13]([OH:16])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)O
Reactant: Cc1ccc([N+](=O)[O-])cc1
Agent: [Br-]
Agent: [NH4+]
Product: O=C(O)c1ccc([N+](=O)[O-])cc1

Procedure:
750 g of p-nitrotoluene was oxidized in 2250 ml of glacial acetic acid, after the addition of 15 g of NH4Br, 4.5 g of Co(OAc)2 . 4H2O and 4.5 g of Mn(OAc)2 . 4H2O, at a reaction temperature of 175° C. The reaction product was washed and dried as before. 795 g (87% of the theory) of brown-discolored p-nitrobenzoic acid was obtained, having a melting point of 235°-36° C. The solution of 1 g of the product in 10 g of dimethylsulfoxide has a value of 40 on the iodine color scale. After recrystallization three times from glacial acetic acid, the melting point was 237°-40° C, while the iodine number remained unchanged.