Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:12]=[C:11](Cl)[C:10]2[C:5](=[C:6]([O:16][CH3:17])[C:7]([O:14][CH3:15])=[CH:8][CH:9]=2)[N:4]=1>O1CCCC1>[Cl:2][C:3]1[N:12]=[C:11]([NH2:1])[C:10]2[C:5](=[C:6]([O:16][CH3:17])[C:7]([O:14][CH3:15])=[CH:8][CH:9]=2)[N:4]=1
Reactant: N
Reactant: COc1ccc2c(Cl)nc(Cl)nc2c1OC
Solvent: C1CCOC1
Product: COc1ccc2c(N)nc(Cl)nc2c1OC

Procedure:
Ammonia was passed into a solution of 2,4-dichloro-7,8-dimethoxyquinazoline (287 g., 1.11 moles) in tetrahydrofuran (6 liters) for five hours at room temperature. After stirring an additional hour the suspension was concentrated in vacuo to 2 liters and filtered. The solid was suspended in 2 liters of water, filtered, washed with water and cold methanol. Recrystallization from dimethylformamide/water yielded 164 g. (62%) of pure product, M.P. 300° (dec.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:27][N:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:27][N:26]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Brc1ccc(OC2CCOCC2)cn1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC2CCOCC2)cn1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 2-bromo-5-(tetrahydro-pyran-4-yloxy)-pyridine (Intermediate 23) in analogy to Example 1a): MS (ISP): 481.2 and 483.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH:7][CH:12]([C:14]2[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])[CH:8]=1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: Cc1ccc(Cl)cc1N
Agent: Br
Product: Cc1ccc(Cl)cc1NC(C)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 59.6 %

Procedure:
5-chloro-2-methylaniline (0.098 mL, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(5-chloro-2-methylphenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (56 mg, 58%) as a white solid. Mass Spectrum: M+H+ 470. NMR Spectrum (DMSOd6): 1.61 (d, 3H), 2.21 (s, 3H), 2.71 (bs, 3H), 2.93 (bs, 3H), 3.52-3.65 (m, 4H), 3.70-3.80 (m, 4H), 5.03-5.11 (m, 1H), 5.55 (d, 1H), 5.62 (s, 1H), 6.19 (d, 1H), 6.49 (dd, 1H), 6.97 (d, 1H), 7.62 (d, 1H), 7.79 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:13]=[C:14]([SH:18])[C:15]([OH:17])=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].O1CCOCC1.II.S(=O)(O)[O-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:9]([O:10][CH2:11][CH3:12])=[CH:8][C:7]2[S:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C=C(S)C(=O)O)cc1OCC
Agent: II
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1cc2cc(C(=O)O)sc2cc1OCC

Procedure:
Two grams of β-(3,4-diethoxyphenyl)-α-mercaptoacrylic acid were dissolved in 68.5 ml. of dioxane. To the solution were added 2.74 g. of iodine. The solution was heated at 60°-70° C. for 22 hours. The reaction was then poured into 550 ml. of water, decolorized with 11.0 g. of sodium bisulfite, and stirred vigorously for several minutes. The crude product was collected by filtration and dissolved in approximately 15 ml. of a warm 10% sodium hydroxide solution. The alkaline solution was treated with decolorizing carbon and filtered. The solution was allowed to stand at refrigerator temperature overnight. The resulting pink crystals were collected and dissolved in water. Dilute hydrochloric acid was added and the resulting precipitate was collected to give 0.59 g. of the desired title product. Two recrystallizations from 95% ethanol gave white needles, m.p. 243°-245° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[S:11][CH:10]=[C:9]([CH:12]=O)[CH:8]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[S:11][CH:10]=[C:9](/[CH:12]=[CH:22]/[CH:23]=[O:24])[CH:8]=1
Reactant: O=Cc1csc(-c2cnccn2)c1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1csc(-c2cnccn2)c1

Procedure:
The title compound is prepared by a procedure analogous to Reference Example 30 by substituting 5-pyrazinyl-3-thiophenecarboxaldehyde (prepared as described in Reference Example 95) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 217 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[I:18]N1C(=O)CCC1=O>C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[I:18])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ncc2c1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Cool a solution of 5-(tert-butyldimethylsilyloxy)-1H-indazole (300.00 g, 1.21 mol) in DCM (4.00 L) to 10° C. in a 10 L jacketed reactor vessel. To the resulting solution add N-iodosuccinimide (298.89 g, 1.33 mol) in portions over 0.5 hours. Stir the mixture at RT for 3 hours to give complete conversion as indicated by liquid chromatography mass spectrometry (LC-MS) and thin layer chromatography (TLC). Cool the mixture to 10° C. and quench with water (2.5 L). Transfer the mixture to a separatory funnel and extract the aqueous layer into DCM (2.5 L). Wash the combined organic extracts with a 10% aqueous sodium thiosulfate solution (5 L) and brine. Dry the organic solution over magnesium sulfate, filter and concentrate in vacuo to afford the title compound as an orange solid. Yield: 388 g (90%). MS (ES) m/z 375 [M+1]+.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:7](COC)[C:6]([O:19][CH3:20])=[CH:5][CH:4]=1.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>>[CH3:20][O:19][C:6]1[C:7]([O:10][CH2:9][O:11][CH3:12])=[C:8]([C:3]([CH2:2][O:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)=[CH:4][CH:5]=1)[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: COCc1c(OC)ccc(CBr)c1C(=O)OC(C)(C)C
Product: COCOc1c(OC)ccc(COc2ccc(-c3ccc(CC(=O)OC)cc3)cc2)c1C(=O)OC(C)(C)C
Yield: 25 %

Procedure:
According to a method similar to Example (40-2), from tert-butyl 6-(bromomethyl)-3-methoxy-2-(methoxymethyl)benzoate (1.20 g, 2.33 mmol) and methyl (4′-hydroxy-1,1′-biphenyl-4-yl)acetate (619 mg, 2.56 mmol) obtained in Example (6-2), tert-butyl 3-methoxy-2-(methoxymethoxy)-6-[({4′-[(methoxycarbonyl)methyl]-1,1′-biphenyl-4-yl}oxy)methyl]benzoate was obtained (306 mg, yield: 25%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(Cl)c1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)Cl)c(Cl)c1Cl
Yield: 100 %

Procedure:
2,3-Dichloro-4-methylbenzoic acid (I70) (5.90 g, 26.2 mmol) and thionyl chloride (30 mL, 411 mmol) were heated at 85° C. for 4 hr in toluene (100 mL). The solvents were removed in vacuo and the residue was azeotroped with toluene (3×100 mL). The residue was used in subsequent steps without further purification assuming 100% yield. Compound not characterised at this step.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:7])[N:6]=1.Cl[CH2:14][C:15]1[CH:16]=[C:17]([CH:32]=[C:33]([O:35][CH2:36][CH3:37])[CH:34]=1)[O:18][CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[CH2:36]([O:35][C:33]1[CH:34]=[C:15]([CH:16]=[C:17]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])[CH:32]=1)[CH2:14][S:1][C:2]1[S:3][C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:7])[N:6]=1)[CH3:37]
Reactant: COC(=O)Cc1sc(S)nc1C
Reactant: CCOc1cc(CCl)cc(OCc2nc(-c3ccccc3)oc2C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(CSc2nc(C)c(CC(=O)OC)s2)cc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A mixture of methyl (2-mercapto-4-methylthiazol-5-yl)acetate (455 mg), 4-(3-chloromethyl-5-ethoxyphenoxymethyl)-5-methyl-2-phenyloxazole (800 mg), potassium carbonate (465 mg) and N,N-dimethylformamide (20 ml) was stirred at room temperature for 2 hrs. The reaction mixture was poured into water, neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [2-[3-ethoxy-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylthio]-4-methylthiazol-5-yl]acetate (1.02 g, yield 87%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[BH4-].[Na+]>C(O)C>[O:3]1[C:4]2([CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]2)[O:11][CH2:1][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCC2(CC1)OCCO2

Procedure:
When n is the bridging group --C(Cl)=CH--, 1,4-cyclohexanedione mono-ethylene ketal is reduced with sodium borohydride in ethanol, yielding the corresponding 1,4-dioxaspiro[4.5]decan-8-ol. The so-prepared alcohol is then treated with methanesulfonyl chloride under basic conditions in methylene chloride, affording 8-methylsulfonyloxy-1,4-dioxaspiro[4.5]decane, which is in turn treated with sodium hydride in tetrahydrofuran, and then is reacted with trimethylsilylacetylene, yielding 8-(trimethylsilylethynyl)-1,4-dioxaspiro[4.5]decane. This compound is then treated with sodium carbonate in methanol to unprotect the ethynyl moiety, affording 8-ethynyl-1,4-dioxaspiro[4.5]decane. The so-prepared ethynyl compound is reacted with an appropriately substituted or unsubstituted phenyl iodide, for example, 3,5-di(trifluoromethyl)phenyl iodide, under basic conditions in the presence of bis(triphenylphosphine)palladium(II) chloride and copper(I) iodide in acetonitrile, and then is treated with 1N hydrochloric acid, yielding the corresponding 4-(phenylethynyl)cyclohexanone. The cyclohexanone is then reacted with cyanoguanidine, as previously described, affording the 2,4-diamino-6-phenylethynyl-5,6,7,8-tetrahydroquinazoline. Chlorination of the 6-phenylethynyl-5,6,7,8-tetrahydroquinazoline, using the methods of J. Cousseau (JCS Faraday II, 1973, 1821, and JCS Perkin I, 1977, 1797), affords the targeted 2,4-diamino-6-[1-chloro-2-phenylethenyl]-5,6,7,8-tetrahydroquinazoline. Example 8 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:10])=[C:4]([NH2:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:11]([N:14]=[C:15]=S)([CH3:13])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]2[N:10]=[C:15]([NH:14][CH:11]([CH3:13])[CH3:12])[NH:9][C:4]=2[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1cc(Cl)cc(Cl)c1N
Reactant: CC(C)N=C=S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: CC(C)Nc1nc2c(Cl)cc(Cl)cc2[nH]1
Yield: 59.9 %

Procedure:
3,5-Dichloro-1,2-phenylenediamine (1.30 g, 7.32 mmol), isopropyl isothiocyanate (0.81 g, 8.00 mmol), 1-cyclohexyl-1-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (4.19 g, 9.89 mmol) and pyridine (25 mL) were used according to general procedure I. The product was recrystallized from 1,4-dioxane to afford 1.07 g (60%) of a white solid. Anal. calcd for C10H11Cl12N3-(0.25 C4H8O2): C, 49.64; H, 4.92; N, 15.79. Found: C, 49.54; H, 4.94; N, 15.79.
Reaction SMILES: C(O[C:6]([C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:20]([CH2:23][N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)=[N:21][S:22][C:10]=2[C:9]=1[OH:33])=[O:7])CCC.[NH2:34][CH2:35][C:36]([OH:38])=[O:37]>>[OH:33][C:9]1[C:10]2[S:22][N:21]=[C:20]([CH2:23][N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[C:11]=2[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:13][C:8]=1[C:6]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:7]
Reactant: CCCCOC(=O)c1nc(-c2ccccc2)c2c(Cn3ccc4ccccc43)nsc2c1O
Reactant: NCC(=O)O
Product: O=C(O)CNC(=O)c1nc(-c2ccccc2)c2c(Cn3ccc4ccccc43)nsc2c1O

Procedure:
The title compound was synthesized in analogy Example 1 from 7-hydroxy-3-indol-1-ylmethyl-4-phenyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester and glycine: MS (m/z) 459.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].[CH3:31][N:32]([CH3:38])[CH:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([N:35]5[CH2:36][CH2:37][CH:33]([N:32]([CH3:38])[CH3:31])[CH2:34]5)[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: CN(C)C1CCNC1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCC(N(C)C)C3)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
A solution of 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide (50 mg, 0.12 mmol) in 3(dimethylamino)pyrrolidine (1 ml) was heated at 120° C. for 18 h in a sealed tube. The reaction was concentrated under vacuum, the residue triturated with water to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-(3-dimethylaminopyrrolidin-1-yl)isonicotinamide (38 mg). NMR; δH [2H6]—DMSO includes 10.28,(1H, s), 8.62,(1H, t), 8.20,(1H, d), 7.93,(2H, d), 7.71,(1H, dd), 7.65,(1H, d), 7.44,(2H, d), 7.30,(1H, d), 6.98,(1H, d), 6.87,(1H, s), 3.72,(1H, m), 3.62,(1H, m), 3.37,(1H, m), 3.16,(3H, m), 2.80,(1H, b), 2.21,(9H, m), 1.81,(1H, m), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 2.55 min, MH+498.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][NH:27][CH3:28]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:27]([CH3:28])[CH3:26])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: CNC
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N(C)C)c2c1

Procedure:
The title compound was prepared in analogy to Example 16-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and dimethylamine. MS obsd. (ESI+) [(M+H)+] 382, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (d, J=7.6 Hz, 1 H), 7.85-7.83 (m, 2 H), 7.73-7.70 (m, 2 H), 7.58-7.55 (m, 2 H), 6.14 (s, 1 H), 5.30 (s, 2 H), 4.51 (s, 2 H), 3.72-3.70 (m, 2 H), 3.29 (s, 6 H), 2.45 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]([O:19][CH3:20])=[O:18])[C:6]2[CH:7]=[CH:8][C:9](=[O:16])[N:10]([CH2:13][CH:14]=O)[C:11]=2[CH:12]=1.[O:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][N:32]([CH:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:35]([O:34][C:33]([N:32]([CH2:31][C:29]1[CH:28]=[CH:27][C:26]2[O:21][CH2:22][CH2:23][O:24][C:25]=2[CH:30]=1)[CH:40]1[CH2:45][CH2:44][N:43]([CH2:14][CH2:13][N:10]2[C:11]3[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([C:17]([O:19][CH3:20])=[O:18])[C:6]=3[CH:7]=[CH:8][C:9]2=[O:16])[CH2:42][CH2:41]1)=[O:39])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: COC(=O)c1cc(OC)cc2c1ccc(=O)n2CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To 10 mL of a chloroform solution containing 472 mg of methyl 7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-5-carboxylate and 374 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 62 μL of acetic acid was added and stirred at room temperature for 1 hour. To the reaction mixture, 352 mg of sodium triacetoxyborohydride was added and stirred for 30 min. Aqueous saturated sodium hydrogen carbonate solution was added and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; ethyl acetate:hexane=2:1], to give 493 mg of methyl 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-5-carboxylate as a white solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CCN(C(C)C)C(C)C>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:23]2[CH2:24][CH2:25][CH2:26][CH:21]([NH:20][C:13](=[O:14])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:22]2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)#[N:7]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccc(C#N)cc2[N+](=O)[O-])C1
Yield: 95 %

Procedure:
Method 1 was followed using 4-chloro-3-nitrobenzonitrile (1.0 eq), 3-(N-Boc-amino) piperidine (1.0 eq), and DIEA (2.4 eq) at 55° C. for 24 hours yielding tert-butyl 1-(4-cyano-2-nitrophenyl)piperidin-3-ylcarbamate (95%). LCMS (m/z): 347.2 (MH+); LC Rt=3.06 min.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[CH3:13][N:14]([CH3:29])[S:15]([C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)[C:23](O)=[O:24])(=[O:17])=[O:16]>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:23](=[O:24])[C:22]2[CH:26]=[C:18]([S:15](=[O:17])(=[O:16])[N:14]([CH3:29])[CH3:13])[CH:19]=[CH:20][C:21]=2[O:27][CH3:28])[CH2:7]1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1ccc(S(=O)(=O)N(C)C)cc1C(=O)O
Product: COc1ccc(S(=O)(=O)N(C)C)cc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 5-dimethylsulfamoyl-2-methoxybenzoic acid.
Reaction SMILES: [N:1]([CH2:4][C:5]1([CH3:23])[NH:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:6]1=[O:22])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][CH2:4][C:5]1([CH3:23])[NH:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:6]1=[O:22]
Reactant: CC1(CN=[N+]=[N-])NC(=O)N(c2ccc(Cl)c(C(F)(F)F)c2)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC1(CN)NC(=O)N(c2ccc(Cl)c(C(F)(F)F)c2)C1=O

Procedure:
5-Azidomethyl-3-(4-chloro-3-trifluoromethyl-phenyl)-5-methyl-imidazolidine-2,4-dione (500 mg, 1.45 mmoL), Ph3P (380 mg, 1.45 mmoL) in THF (5 mL) and water (1 mL) was heated to reflux for 4 hrs. The solid was filtered through a pad of Celite. The Celite was washed with ethyl acetate. The combined filtrate was concentrated to give a colorless oil, which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[F:33][C:2]([F:32])([F:1])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: C1CNCCN1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCNCC2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-piperazin-1-yl-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and piperazine following General Procedure C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[C:13]([Cl:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=2[Cl:18])=[CH:5][CH:4]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[Cl:18][C:9]1[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[C:13]([Cl:14])[C:8]=1[O:7][C:6]1[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[C:4]([S:28]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH:5]=1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)c1ccc(F)cc1
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 29.1 %

Procedure:
A mixture of 4-(4-methoxy-phenoxy)-3,5-dichloro-nitrobenzene (1 g, 3.4 mmol), p-fluorophenylsulfonyl chloride (1.33 g, 6.8 mmol) and Eaton's reagent (20 mL) was stirred at 110° C. for 4.5 h and the solution turned brown. The brown solution was poured into ice water and extracted with EtOAc (3×30 mL). The combined extracts were washed with sat'd sodium bicarbonate (3×50 mL), brine (50 mL), dried and concentrated. The residue was purified by chromatography (20% EtOAc in Hexanes) to give the title compound of Step A (468 mg). MS (APCI−) Calc.: 471.0, Found: 470.0 (M−1).