Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[C:21]([F:22])=[CH:20][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3OC)[C:27]3[CH:32]=[CH:31][N:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[C:18]([F:44])[CH:17]=2)[C@@H:11]([C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[C:21]([F:22])=[CH:20][C:19]([S:23]([NH:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][N:28]=3)(=[O:24])=[O:25])=[C:18]([F:44])[CH:17]=2)[C@@H:11]([C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CC[C@@H](OCc4ccccc4)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1C[C@H](OCc2ccccc2)CC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 100.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R,4R*)-4-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (137 mg, 0.194 mmol) prepared in Example 112b, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (108 mg, 70%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH3:27])[CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([O:19]C)=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[K+]>CO.O.C1COCC1>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]([CH3:27])[CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([OH:19])=[O:18])(=[O:13])=[O:14])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)O)c2ccccc2)cc1
Yield: 74 %

Procedure:
A solution of 1.50 g of methyl 2-[{[4-(2-butynyloxy)phenyl]-sulfonyl}(methyl)amino]-2-phenylacetate and 1.50 g of KOH in a methanol/water/THF mixture was stirred at room temperature for 18 hours. The solution was then evaporated, the residue was dissolved in water and then acidified with 2N hydrochloric acid, and the precipitate was collected and dried to give 1.07 g of 2-[{[4-(2-butynyloxy)- phenyl]sulfonyl}(methyl)amino]-2-phenylacetic acid as colorless crystals,
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:36][C:37]1[CH:38]=[CH:39][C:40](/[C:45](/I)=[CH:46]/[CH2:47][OH:48])=[N:41][C:42]=1[O:43][CH3:44]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[C:1]([C:5]1[CH:10]=[CH:9][C:8](/[C:45](/[C:40]2[CH:39]=[CH:38][C:37]([Cl:36])=[C:42]([O:43][CH3:44])[N:41]=2)=[CH:46]\[CH2:47][OH:48])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: COc1nc(/C(I)=C/CO)ccc1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1nc(/C(=C/CO)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 101.6 %

Procedure:
4-tert-Butylphenylboronic acid (3.5 g), tris(dibenzylideneacetone)dipalladium(0) (183 mg), tri(2-furyl)phosphine (280 mg) and cesium carbonate (1.98 g) were added to a solution of (2Z)-3-(5-chloro-6-methoxypyridin-2-yl)-3-iodoprop-2-en-1-ol (881 mg) in 1,4-dioxane (20 mL)-water (10 mL) in a nitrogen atmosphere, and the mixture was stirred at an external temperature of 65° C. for 1.5 hours. The reaction solution was left to cool, diluted with ethyl acetate and filtered. The filtrate was washed with brine and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→1:1) to give the title compound as a light yellow powder (912 mg, 91%).
Reaction SMILES: [CH3:1][C@:2]1([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[N:14][C:15]([NH:18]/[N:19]=[CH:20]/[C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[C:24]([O:31][CH:32]([CH3:34])[CH3:33])[CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:16][CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:3]1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[CH3:1][C@:2]1([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:17]=[CH:16][C:15]3[N:14]([C:20]([C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[C:24]([O:31][CH:32]([CH3:34])[CH3:33])[CH:25]=[CH:26][CH:27]=5)[N:22]=4)=[N:19][N:18]=3)[CH:13]=2)[C:8]([F:11])([F:10])[F:9])[CH2:3]1
Reactant: CC(C)Oc1cccc2ccc(/C=N/Nc3ccc([C@H](N4CC[C@](C)(NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)nc12
Solvent: Ic1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)Oc1cccc2ccc(-c3nnc4ccc([C@H](N5CC[C@](C)(NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a stirred solution of tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(6-((E)-2-((8-isopropoxyquinolin-2-yl)methylene)hydrazinyl)pyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (1.33 g, 2.27 mmol) in DCM (20 mL) was added iodo benzene diacetate (0.949 g, 2.95 mmol). The reaction mixture was stirred at ambient temperature for 2 hours and then partitioned between ethyl acetate and saturated aqueous NaHCO3. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by chromatography (1:3 hexane/ethyl acetate) to give tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(3-(8-isopropoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (1.30 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=2)=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15]3)=[CH:10][CH:9]=2)[CH:7]=1.Cl.C(OCC)(=O)C.[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=2)=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][NH:14][CH2:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1ccnc(COc2ccc(F)cc2-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccnc(COc2ccc(F)cc2-c2ccc3c(c2)CNCC3)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl 7-(5-fluoro-2-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate (0.169 g) was dissolved in dioxane (1 ml). This was ice cooled before adding dropwise a solution of hydrogen chloride in dioxane (2 ml). This was stirred at room temperature overnight before concentrating in vacuo. The residue obtained was dissolved in water and backwashed with ethyl acetate. The aqueous layer was neutralised with aqueous sodium hydroxide (1M) and extracted with ethyl acetate. The organics were concentrated in vacuo and purified by preparative HPLC. Appropriate fractions were concentrated, neutralised with aqueous sodium bicarbonate and extracted with ethyl acetate. The organics were concentrated in vacuo to yield the title compound, 0.061 g (47%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH2:18]([O:20][C:21](=O)[O:22]CC)[CH3:19]>>[C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH2:2][C:21]([O:20][CH2:18][CH3:19])=[O:22])=[CH:5][CH:6]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
14.7 g (75.0 mmol) of 4-acetylbiphenyl is dissolved in 150 mL of diethylcarbonate. Under protective gas, a total of 6.50 g (150 mmol) sodium hydride in oil (55%) is added batchwise at 0° C. The mixture is kept for 5 minutes at 0° C., then stirred for 2 hours at 80° C. After cooling, the mixture is poured onto water and extracted with methylene chloride; the organic phase is washed with water and finally dried over sodium sulfate. The solvent is eliminated, the residue is suspended in water and neutralized with 1N hydrochloric acid. The aqueous phase is extracted with diethyl ether, the organic phase is dried over sodium sulfate, and finally the solvent is eliminated. Lastly the residue is recrystallized from petroleum ether and the product is dried in vacuo at 50° C. Yield: 15.3 g (76% of theory); Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate=5:2); m.p. 75° C.-77° C.; C17H16O3; EII mass spectrum: m/z=269 [M+H]+.
Reaction SMILES: O=C1C2C3C(C(OC)=O)=CC=CC=3NC=2CNC1.[C:19]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C[N:27]1[CH2:39][C:38]2[NH:37][C:36]3[CH:35]=[CH:34][CH:33]=[C:32]4[C:40](=[O:43])[NH:41][N:42]=[C:29]([C:30]=2[C:31]=34)[CH2:28]1>>[CH:19]1([N:27]2[CH2:39][C:38]3[NH:37][C:36]4[CH:35]=[CH:34][CH:33]=[C:32]5[C:40](=[O:43])[NH:41][N:42]=[C:29]([C:30]=3[C:31]=45)[CH2:28]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C1CCCCC1
Reactant: CN1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Agent: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CNC3
Product: O=C1NN=C2CN(C3CCCCC3)Cc3[nH]c4cccc1c4c32

Procedure:
Compound 53 was prepared from methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and cyclohexanone according to the procedures similar to those for Compound 44. 1H NMR (DMSO-d6) δ 11.7 (s, 1H), 9.86 (s, 1H), 7.47 (d, 1H, J=7.8 Hz), 7.42 (d, 1H, J=7.8 Hz), 7.12 (t, 1H, J=7.8 Hz), 3.91 (s, 2H), 3.38 (s, 2H), 2.50-2.56 (m, 1H), 1.58-1.84 (m, 4H), and 1.11-1.31 (m, 6H). MS (ESI) m/e [M+1]+ 309.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.ClC1C=C(Cl)C=CC=1C[N:23](CC)CCN>>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH2:23])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CCN(CCN)Cc1ccc(Cl)cc1Cl
Product: COc1cc(N)c(Cl)cc1C(N)=O

Procedure:
By following general method B using 1.0 g. of 4-amino-5-chloro-2-methoxybenzoic acid and 1.2 g. of N-(2',4'-dichlorophenylmethyl)-N-ethylethylenediamine, 1.6 g. of N-[2-(N'-2',4'-dichlorophenylmethyl)-N'-ethylamino)ethyl]-4-amino-5-chloro-2-methoxybenzamide was obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.[F:23][C:24]([F:66])([F:65])[C:25]1[CH:26]=[C:27]([CH:62]=[CH:63][CH:64]=1)[CH2:28][NH:29][C:30](=[O:61])[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:37]2[CH:42]=[C:41]([N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[CH:40]=[CH:39][C:38]=2[NH:49][C:50](=[O:60])[C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([CH2:57][NH:58][CH3:59])[CH:52]=2)[CH:32]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:59][N:58]([CH2:57][C:53]1[CH:52]=[C:51]([CH:56]=[CH:55][CH:54]=1)[C:50]([NH:49][C:38]1[CH:39]=[CH:40][C:41]([N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[CH:42][C:37]=1[C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][N:34]=1)[C:30]([NH:29][CH2:28][C:27]1[CH:62]=[CH:63][CH:64]=[C:25]([C:24]([F:65])([F:23])[F:66])[CH:26]=1)=[O:61])=[O:60])[C:8](=[O:10])[CH2:7][N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1
Reactant: O=C(O)CN1CCOCC1
Reactant: CNCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1)C(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 38.3 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 2-morpholinoacetic acid (25.0 mg, 0.17 mmol, 1.00 equiv) in dichloromethane (10 mL), EDC.HCl (50.0 mg, 0.26 mmol, 1.50 equiv), 4-dimethylaminopyridine (32.0 mg, 0.26 mmol, 1.50 equiv), and N-(3-(trifluoromethyl)benzyl)-2-(2-(3-((methylamino)methyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (1000 mg, 1.66 mmol, 1.00 equiv). The resulting solution was stirred for 6 h at 25° C. in an oil bath. The resulting solution was diluted with 50 mL of dichloromethane. The resulting mixture was washed with 2×30 mL of aqueous NH4Cl. The resulting mixture was washed with brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The crude product (120 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 47.4 mg (26%) of a pale-yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.90-8.98 (m, 1H), 8.57-8.64 (m, 1H), 8.40 (s, 1H), 7.84-8.00 (m, 4H), 7.54-7.72 (m, 7H), 4.72-4.76 (m, 4H), 4.36-4.38 (m, 2H), 3.96 (m, 4H), 3.58-3.61 (m, 4H), 3.01 (s, 3H), 1.99-2.00 (m, 4H), 1.75 (m, 2H). MS (ES, m/z) 729 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.CC([O-])=O.[K+].C([O-])([O-])=O.[K+].[K+].Cl[C:45]1[CH:50]=[N:49][CH:48]=[CH:47][N:46]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.C1COCC1>[C:11]([O:10][C:8](=[O:9])[C:5]1[CH:4]=[CH:3][C:2]([C:45]2[CH:50]=[N:49][CH:48]=[CH:47][N:46]=2)=[CH:7][N:6]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Clc1cnccn1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(-c2cnccn2)cn1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
The 250 mL flask was charged with tert-butyl 5-bromopicolinate 34h-4 (12.9 g, 50 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (13.9 g, 55 mmol), KOAc (9.8 g, 100 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.408 g, 0.5 mmol) and THF (80 mL). The flask was sealed under nitrogen and the mixture was stirred at 80° C. for 24 hours. After completion of the reaction, it was cooled to room temperature and filtered through Celite. The filtrate was taken in 500 mL 4-necked RB flask and charged with aqueous K2CO3 solution (13.8 g in 100 ml Of water), 2-chloropyrazine (6.8 g, 60 mmol), and PdCl2(dppf)-CH2Cl2 adduct (0.204 g, 0.25 mmol). The reaction mixture was stirred at 64° C. for 2 h under nitrogen, cooled to room temperature and filtered through Celite. The filtrate was diluted with i-PrOAc (100 mL) and the aqueous layer separated. The organic layer was washed with water (2×100 mL), concentrated to ˜20 mL of volume and diluted with heptane (200 mL). The solid was collected by filtration, washed with heptane (50 mL), and dried at 40° C. to obtain 34h-1 as a pale yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=[N:8][O:9][C:10]=1[CH3:11])=O)C.C(OC(C1C(C2C=CC=CC=2F)=NOC=1C)=O)C>>[F:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[C:7]1[C:6]([CH2:4][OH:3])=[C:10]([CH3:11])[O:9][N:8]=1
Reactant: CCOC(=O)c1c(-c2cc(F)ccc2F)noc1C
Agent: CCOC(=O)c1c(-c2ccccc2F)noc1C
Product: Cc1onc(-c2cc(F)ccc2F)c1CO
Yield: 21.4 %

Procedure:
As described for example 84d, 3-(2,5-difluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (18 g, 67.4 mmol) was converted, instead of 3-(2-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester, to the title compound (3.25 g, 21%) which was obtained as a yellow oil. MS: m/e=226.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[C:7](=[O:14])[C:6]([C:15]([O:17]CC)=O)=[C:5]2[OH:20].[C:21]([NH:30][NH2:31])(=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[C:7](=[O:14])[C:6]([C:15]([NH:31][NH:30][C:21](=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:17])=[C:5]2[OH:20]
Reactant: CCCCCCCC(=O)NN
Reactant: CCOC(=O)c1c(O)c2cc(Cl)ccc2n(CC)c1=O
Product: CCCCCCCC(=O)NNC(=O)c1c(O)c2cc(Cl)ccc2n(CC)c1=O

Procedure:
Reagents: Comp 38 (0.68 mmols, 0.2 g); octanoyl hydrazine (0.74 mmols, 0.119 g). Yield: 0.19 g (70%), white solid, m.p.=160° C.-161° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]2[C:24]2[CH:29]=[C:28]([CH3:30])[C:27]([O:31][CH2:32][CH2:33][OH:34])=[C:26]([CH3:35])[CH:25]=2)=[CH:9][CH:8]=1>C(Cl)Cl>[CH3:1][S:2]([O:34][CH2:33][CH2:32][O:31][C:27]1[C:26]([CH3:35])=[CH:25][C:24]([C:14]2[N:13]([C:10]3[CH:11]=[CH:12][C:7]([N:6]([S:2]([CH3:1])(=[O:4])=[O:3])[S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][CH:9]=3)[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:29][C:28]=1[CH3:30])(=[O:4])=[O:3]
Reactant: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(N)cc2)cc(C)c1OCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc2)cc(C)c1OCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.7 %

Procedure:
TEA (0.24 mL, 1.70 mmol) followed by methanesulfonyl chloride (0.13 mL, 1.70 mmol) were added to a solution of 3-(4-aminophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (0.230 g, 0.57 mmol) in CH2Cl2 (10 mL). After stirring for 6 hours at room temperature, the mixture was concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 2% to 8% MeOH in CH2Cl2, afforded 2-(2,6-dimethyl-4-(3-(4-(N-(methylsulfonyl)methylsulfonamido) phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)ethyl methanesulfonate (0.280 g, 77%).
Reaction SMILES: [Li]N([Si](C)(C)C)[Si](C)(C)C.C1COCC1.[CH3:16][O:17][C:18]1([O:26][CH3:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=[O:25].[CH2:28]([O:30][C:31](=[O:37])[C:32](OCC)=[O:33])[CH3:29].OP([O-])(O)=O.[K+]>CCOCC>[CH3:27][O:26][C:18]1([O:17][CH3:16])[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]([C:32](=[O:33])[C:31]([O:30][CH2:28][CH3:29])=[O:37])[C:19]1=[O:25]
Reactant: COC1(OC)CCCCCC1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(=O)C1CCCCC(OC)(OC)C1=O
Reaction time: 8 h
Yield: 65 %

Procedure:
1M LiN(TMS)2 in THF (28.5 mL, 28.5 mmol) were added dropwise at −50° C. to a solution of 2,2-dimethoxycycloheptanone (4.10 g, 23.8 mmol) in 25 mL of Et2O under argon. After 30 minutes at the same temperature, 3.55 mL of diethyloxalate were also added under stirring. The solution was kept at room temperature overnight. 10% solution of KH2PO4 (20 mL) were then added and the resulting solution extracted with Et2O (3×50 mL). The organic layer was dried over Na2SO4 and evaporated to dryness. The crude was purified by chromatography on a silica gel column (eluant: AcOEt/cyclohexane 1/9) to afford 3.98 g (65% yield) as a colorless oil.
Reaction SMILES: [CH3:1][S-:2].[Na+].F[C:5]1[CH:10]=[CH:9][C:8]([I:11])=[C:7]([Cl:12])[CH:6]=1>O>[Cl:12][C:7]1[CH:6]=[C:5]([S:2][CH3:1])[CH:10]=[CH:9][C:8]=1[I:11]
Reactant: Fc1ccc(I)c(Cl)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Product: CSc1ccc(I)c(Cl)c1
Reaction time: 20 h

Procedure:
Sodium methanethiolate (5 g) was added to a solution of 4-fluoro-2-chloro-iodobenzene (18.3 g) and stirred for 20 h. The mixture was poured into water, extracted with ether, washed with brine, dried (MgSO4) and evaporated. Yield 18.5 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])O[C:7](=[O:12])[C:6]=2[CH:13]=1.[CH3:14][O:15][C:16]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:17]=1[CH2:18][NH:19][CH2:20]C(O)=O>CC1C=CC(C)=CC=1>[CH3:14][O:15][C:16]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:17]=1[CH2:18][N:19]1[C:7](=[O:12])[C:6]2[CH:13]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[NH:10][C:9](=[O:11])[CH2:20]1
Reactant: COc1ccc(CNCC(=O)O)c(OC)c1
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Solvent: Cc1ccc(C)cc1
Product: COc1ccc(CN2CC(=O)Nc3ccc(C)cc3C2=O)c(OC)c1
Temperature: 150 °C

Procedure:
A suspension of 6-methyl-2H-3,1-bezoxazine-2,4(1H)-dione (18.3 g, 103 mmol) containing (2,4-dimethoxy-benzylamino)-acetic acid (25.6 g, 114 mmol) in p-xylene (125 mL) was heated under reflux (150° C.) for 2.5 h. After cooling to room temperature the precipitate was filtered off and washed with p-xylene (2×20 ml). Yield: 34.1 g (97%). m/z 341 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]([NH:26][NH2:27])=[O:25])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.CO[C:30](OC)(OC)[CH2:31][Cl:32]>>[Cl:32][CH2:31][C:30]1[O:25][C:24]([C:4]2[CH:5]=[C:6]3[C:10](=[C:2]([CH3:1])[CH:3]=2)[C:9](=[O:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:15][CH:14]=2)[CH2:7]3)=[N:26][N:27]=1
Reactant: Cc1cc(C(=O)NN)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: COC(CCl)(OC)OC
Product: Cc1cc(-c2nnc(CCl)o2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2

Procedure:
7-Methyl-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid hydrazide (200.0 mg, 0.527 mmol) was stirred with trimethoxy chloroethane (2.0 mL) at 120° C. for two hours. The reaction was concentrated and column chromatography (50% EtOAc/Hexanes) provided the title compound as a yellow solid (28.0 mg). 1H NMR (300 MHz, CDCl3): δ 7.94 (s, 2H), 7.38 (d, 2H), 7.21 (d, 2H), 4.81 (s, 4H), 4.34 (s, 2H), 2.85 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH2:22][CH:23]1[NH:27][CH:26]([CH3:28])[CH2:25][CH2:24]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:27]2[CH:23]([NH2:22])[CH2:24][CH2:25][CH:26]2[CH3:28])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC1CCC(N)N1
Product: CC1CCC(N)N1c1c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c2c1F
Yield: 40 %

Procedure:
The condensation of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with 5-amino-2-methyl-pyrrolidine in a similar manner as described in example 1 gave the titled product. Yield 40%, m.p 224–30° C., C18H20F2N4O3, m/z 379. (M+1)
Reaction SMILES: O=[C:2]1[NH:7][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:5][C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]1[CH:20]([CH2:25][CH2:26][CH3:27])[C:21]([O:23][CH3:24])=[O:22].P(Cl)(Cl)([Cl:30])=O.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:30][C:2]1[C:3]([CH:20]([CH2:25][CH2:26][CH3:27])[C:21]([O:23][CH3:24])=[O:22])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[N:7]=1
Reactant: CCCC(C(=O)OC)c1c(-c2ccccc2)nc(N2CCCCC2)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: CCCC(C(=O)OC)c1c(Cl)nc(N2CCCCC2)nc1-c1ccccc1

Procedure:
To a suspension of methyl 2-(6-oxo-4-phenyl-2-(piperidin-1-yl)-1,6-dihydropyrimidin-5-yl)pentanoate (1.74 g; 4,71 mmol) in dry toluene (10 mL) under nitrogen atmosphere were carefully added phosphorus oxychloride (4.38 mL; 47.1 mmol) and dimethylaniline (0.476 mL; 3.77 mmol) and the reaction mixture was heated to reflux for 3 h. The volatiles were removed under reduced pressure (while the reaction mixture was still at elevated temperature), the residue was cooled in an ice-bath and quenched by adding crushed ice and a saturated solution of sodium hydrogen carbonate until neutralization. The aqueous layer was extracted with ethyl acetate, the organics were collected, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-10%) in heptane furnished 0.040 g (1.6%, over 3 last steps) of the title compound as a yellow oil.