Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Br:12]N1C(=O)CCC1=O>S(=O)(=O)(O)O>[Br:12][C:4]1[C:5]([CH3:11])=[C:6]([CH:10]=[C:2]([F:1])[CH:3]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(F)cc1C(=O)O
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: Cc1c(Br)cc(F)cc1C(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of 5-fluoro-2-methyl-benzoic acid (20 g, 130 mmol) in conc. sulfuric acid (200 mL) was added N-bromosuccinimide (24.3 g, 136 mmol) portionwise. The resulting mixture was stirred at 0° C. for 3 hrs, then warmed to room temperature and stirred for 16 hrs. Then the mixture was poured slowly into ice water (2 L), and extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated to provide 3-bromo-5-fluoro-2-methyl-benzoic acid, which was used directly in the next step.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:4])=[O:3].S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]2[N:34]=[C:33]([NH:35][CH2:36][CH2:37][C:38]3[NH:39][CH:40]=[N:41][CH:42]=3)[C:32]([Br:43])=[CH:31][N:30]=2)=[CH:24][CH:23]=1>CC(N(C)C)=O>[Br:43][C:32]1[C:33]([NH:35][CH2:36][CH2:37][C:38]2[NH:39][CH:40]=[N:41][CH:42]=2)=[N:34][C:29]([NH:28][C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:9](=[O:11])[C:8]3[CH:12]=[CH:13][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[C:6]([N+:14]([O-:16])=[O:15])[CH:7]=3)=[CH:27][CH:26]=2)=[N:30][CH:31]=1
Reactant: Nc1ccc(Nc2ncc(Br)c(NCCc3cnc[nH]3)n2)cc1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Nc3ncc(Br)c(NCCc4cnc[nH]4)n3)cc2)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 23.7 %

Procedure:
4-Methanesulfonyl-3-nitro-benzoic acid (72 mg, 0.29 mmole) was dissolved in DMA (3 ml) and thionyl chloride (0.29 mmole) was added at ambient temperature. After the mixture was stirred for 5 minutes N2-(4-Amino-phenyl)-5-bromo-N4-[2-(3H-imidazol-4-yl)-ethyl]-pyrimidine-2,4-diamine (100 mg, 0.26 mmole, prepared according to procedure 21) was added and the reaction was allowed to stir overnight. After extraction with bicarbonate solution and ethyl acetate (3×) the combined organic layers were dried over magnesium sulfate and the solvent was removed under reduced pressure. The crude product was purified by flashmaster chromatography on silica gel to provide 37 mg of N-(4-{5-Bromo-4-[2-(3H-imidazol-4-yl)-ethylamino]-pyrimidin-2-ylamino}-phenyl}-4-methanesulfonyl-3-nitro-benzamide (23% yield). ESI-MS: 602.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27](O)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[CH3:37][NH:38][CH3:39].C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([N:38]([CH3:39])[CH3:37])=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Reactant: CNC
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)N(C)C)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and dimethylamine using diethyl cyanophosphonate as a coupling reagent. Mass: 536.03 (M+H).
Reaction SMILES: Cl.[C:2]1([NH:8][CH:9]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:10]([OH:12])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:43]12[CH2:50][CH2:49][CH:46]([CH2:47][CH2:48]1)[C@@H:45](O)[CH2:44]2>C1COCC1>[C:2]1([NH:8][CH:9]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:10]([O:12][C@@H:45]2[CH:46]3[CH2:49][CH2:50][N:43]([CH2:48][CH2:47]3)[CH2:44]2)=[O:11])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(Nc1ccccc1)c1cccs1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1cccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.2 %

Procedure:
2-(Phenylamino)-2-(thiophen-2-yl)acetic acid hydrochloride (I29) (359 mg, 1.33 mmol), DCC (330 mg, 1.60 mmol), and HOBT (245 mg, 1.60 mmol) were dissolved in THF (15 ml). (R)-quinuclidin-3-ol (339 mg, 2.66 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. HOBT (20.4 mg, 0.13 mmol) and DCC (33.0 mg, 0.16 mmol) were added again and the mixture was stirred for additional 8 hours. HOBT (20.4 mg, 0.13 mmol), DCC (33.0 mg, 0.16 mmol), (R)-quinuclidin-3-ol (16.9 mg, 0.13 mmol) were added, and the mixture is stirred for additional 16 hours. THF is evaporated, and the resulting crude oil was dissolved in EtOAc and washed with water and brine. The organic phase was recovered, dried over Na2SO4, filtered and evaporated. The crude was first purified by flash chromatography (DCM/MeOH=9/1) and then by preparative HPLC. The pure fractions were collected and evaporated. The resulting TFA salt was dissolved in THF and passed through a PL-HCO3 cartridge (Varian, 200 mg, 1.8 mmol/g HCO3−). THF was evaporated, and the product was dissolved in dioxane (2 ml) and 4M HCl in dioxane (2 ml) was added. The solvent was evaporated, and the residue was dried under vacuum for 24 hours to obtain the title compound (33 mg, 7% yield, mixture of diastereomers).
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1=[O:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1nc2ccccc2[nH]c1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2ccccc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
A solution of 3.90 g of ethyl 1,2-dihydro-2-oxoquinoxaline-3-carboxylate in 25 ml of N,N-dimethylformamide was added dropwise to a suspension of 0.79 g of 60% sodium hydride/oil in 10 ml of N,N-dimethylformamide at room temperature over 30 minutes. After stirring at room temperature for 30 minutes, 3.36 g of benzyl bromide was added dropwise over 10 minutes, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue, after addition of ethyl acetate, was washed with water, 1 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (silica gel; Wakogel C200 (manufactured by Wako Pure Chemicals), developing solvent; hexane−ethyl acetate=10:1−2:1) and recrystallized from ethyl acetate−hexane to give 3.77 g of ethyl 1-benzyl-1,2-dihydro-2-oxoquinoxaline-3-carboxylate.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[N:13]=[C:12]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=[C:10]([C:22]2[C:23]([Cl:30])=[CH:24][C:25]([Cl:29])=[C:26]([OH:28])[CH:27]=2)[N:9]=1.Br[CH2:32][C:33]#[N:34]>CN(C)C=O>[NH2:7][C:8]1[N:13]=[C:12]([S:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:11]=[C:10]([C:22]2[C:23]([Cl:30])=[CH:24][C:25]([Cl:29])=[C:26]([CH:27]=2)[O:28][CH2:32][C:33]#[N:34])[N:9]=1
Reactant: Nc1nc(SCc2ccccc2)nc(-c2cc(O)c(Cl)cc2Cl)n1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CCOc1cc(-c2nc(N)nc(SCc3ccccc3)n2)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
Cesium carbonate (12 mg) was added to a dimethylformamide solution (1 mL) of 5-(4-amino-6-benzylsulfanyl-[1,3,5]triazin-2-yl)-2,4-dichlorophenol (11 mg) obtained in Step 4 described above. A solution of α-bromoacetonitrile (3.6 mg) in dimethylformamide (0.2 mL) was added, and the resulting mixture was stirred at room temperature for 3 hours. After dilution with ethyl acetate (7 mL), the mixture was washed in succession twice with water (6 mL) and once with brine (3 mL). The mixture was then pre-dried over anhydrous sodium sulfate and filtered. The solvent was distilled off. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=8:2) to give [5-(4-amino-6-benzylsulfanyl-[1,3,5]triazin-2-yl)-2,4-dichlorophenoxy]-acetonitrile (11 mg) as white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:28])=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=3[CH3:27])[C:19]([NH:21][CH2:22][CH3:23])=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1.[I-].[K+].[CH3:31][NH:32][CH:33]([CH3:35])[CH3:34]>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:22]([NH:21][C:19](=[O:20])[C:18]1[CH:24]=[CH:25][C:26]([CH3:27])=[C:16]([N:11]2[CH:10]=[C:9]([CH3:28])[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:32]([CH:33]([CH3:35])[CH3:34])[CH3:31])=[CH:6][CH:7]=3)[C:12]2=[O:15])[CH:17]=1)[CH3:23]
Reactant: CCNC(=O)c1ccc(C)c(-n2cc(C)c3ccc(OCCCl)cc3c2=O)c1
Reactant: CNC(C)C
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc(C)c(-n2cc(C)c3ccc(OCCN(C)C(C)C)cc3c2=O)c1
Temperature: 150 °C

Procedure:
A mixture of 3-[7-(2-chloroethoxy)-4-methyl-1-oxoisoquinolin-2(1H)-yl]-N-ethyl-4-methylbenzamide (90 mg), potassium iodide (75 mg), and N-methylisopropylamine (0.14 ml) were stirred in DMA (2 ml) and heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 150° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water (×5), brine (×2), dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting using initially 10% methanol/ethyl acetate and then a 99:1 mixture of 110% methanol/ethyl acetate and aqueous ammonia solution gave N-ethyl-3-[7-{2-[isopropyl(methyl)amino]ethoxy}-4-methyl-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzamide (68 mg) as a cream solid; NMR Spectrum: (DMSOd6) 0.98 (d, 6H), 1.12 (t, 3H), 2.11 (s, 3H), 2.25 (s, 3H), 2.27 (s, 3H), 2.78 (t, 2H), 2.85 (m, 1H), 3.29 (m, 2H), 4.15 (m, 2H), 7.10 (s, 1H), 7.45-7.51 (m, 2H), 7.70-7.77 (m, 3H), 7.88 (d, 1H), 8.47 (t, 1H); Mass Spectrum: M+H+ 436.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH2:10][OH:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1>C(O)C.[Pd]>[O:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH2:10][OH:11])[CH:9]=[C:4]2[CH2:3][CH2:2]1
Reactant: OCc1cc2ccoc2cn1
Agent: [Pd]
Solvent: CCO
Product: OCc1cc2c(cn1)OCC2

Procedure:
Furo[2,3-c]pyridin-5-ylmethanol (1.29 g, 8.7 mmol) was dissolved in ethanol (50 ml) and hydrogenated at rt, 1 atmosphere over 10% palladium on charcoal paste for 18 h. The mixture was filtered through kieselguhr and the filtrate evaporated to dryness, to give (1.31 g, 100%).
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C:7]2[CH2:8][CH2:9][N:10](C(OC(C)(C)C)=O)[CH2:11][CH2:12][C:6]=2[C:5]2[CH:20]=[CH:21][C:22]([N:24]3[CH:29]=[CH:28][C:27]([C:30]4[N:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=4)=[CH:26][C:25]3=[O:40])=[N:23][C:4]1=2>CO.CCOCC>[ClH:1].[CH3:2][N:3]1[C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[C:5]2[CH:20]=[CH:21][C:22]([N:24]3[CH:29]=[CH:28][C:27]([C:30]4[N:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=4)=[CH:26][C:25]3=[O:40])=[N:23][C:4]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nn5)cc4=O)nc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nn5)cc4=O)nc31)CCNCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 94 %

Procedure:
1.25 M HCl in MeOH (4.3 mL) was added to tert-butyl 10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (47 mg, 0.087 mmol), and the resulting solution was stirred under N2 at ambient temperature for 20 h. The solution was diluted with Et2O (25 mL), and the resulting solids were collected by filtration to provide the title compound (39 mg, 94%) as a yellow solid: mp 300-305° C. dec; 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 2H), 8.71 (d, J=9.0 Hz, 1H), 8.47 (d, J=9.0 Hz, 1H), 8.12-8.10 (m, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.23 (dd, J=7.0, 2.0 Hz, 1H), 3.77 (s, 3H), 3.46-3.41 (m, 2H), 3.38-3.34 (m, 2H), 3.32-3.30 (m, 2H, overlapped with solvent), 3.17 (t, J=6.0 Hz, 2H); ESI MS m/z 441 [M+H]+; HPLC (Method A)>99% (AUC), tR=12.8 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19]Br)[CH3:16]>CS(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:19][CH:18]([O:21][CH2:22][CH3:23])[O:17][CH2:15][CH3:16])[CH:9]=1
Reactant: CCOC(CBr)OCC
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(COc1cccc(Br)c1)OCC
Temperature: 160 °C
Yield: 71.9 %

Procedure:
A mixture of potassium carbonate (1.5 g, 10.9 mmol), 3-bromophenol (1.73 g, 10.0 mmol) and bromoacetaldehyde diethyl acetal (1.5 ml, 9.67 mmol) in dimethylsulphoxide (10 ml) was heated at 160° C. for 1½ hours. The cooled reaction was partitioned between water (50 ml) and ethyl acetate (100 ml), and the phases separated. The aqueous layer was extracted with ethyl acetate (50 ml), the combined organic solutions washed consecutively with 1N sodium hydroxide solution, water (2×), brine and then dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by medium pressure column chromatography on silica gel using an elution gradient of ether:pentane (0:100 to 5:95) to afford the title compound (2.01 g, 72%).
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH2:15]([O:22][C:23](=[O:47])[CH2:24][CH:25]([NH:30][C:31](=[O:46])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH:40][C:41]1[CH:45]=[CH:44][S:43][CH:42]=1)[CH2:26][N:27]([CH3:29])[CH3:28])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:15]([O:22][C:23](=[O:47])[CH2:24][CH:25]([NH:30][C:31](=[O:46])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]1[CH:45]=[CH:44][S:43][CH:42]=1)[CH2:26][N:27]([CH3:28])[CH3:29])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN(C)CC(CC(=O)OCc1ccccc1)NC(=O)CCCCCCCC=Cc1ccsc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CC(CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCCc1ccsc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 111.8 %

Procedure:
Triethylsilane (0.23 mL, 1.43 mmol) and trifluoroacetic acid (0.21 mL, 2.9 mmol) were added to a solution of 4-dimethylamino-3-(10-thiophen-3-yl-dec-9-enoylamino)-butyric acid benzyl ester (67 mg, 0.14 mmol) in toluene (8 mL). The reaction mixture was stirred at room temperature for 12 hours after which time the solution was added to cold saturated aq. sodium bicarbonate solution. The aqueous phase was separated and extracted twice with dichloromethane. The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 4-dimethylamino-3-(10-thiophen-3-yl-decanoylamino)-butyric acid benzyl ester (74 mg), m/e=473.3 ([M+H]+).
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]([CH3:22])[CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:35]2[C:36]([CH2:41]CCC)=[N:37]OC=2C)=NC=1.C(N)(C)C>>[CH:36]([NH:37][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]([CH3:22])[CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1)([CH3:41])[CH3:35]
Reactant: CCCC(C)c1noc(C)c1COc1ccc(C(=O)OC)cn1
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Solvent: CC(C)N
Product: CCCC(C)c1noc(C)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 17 %

Procedure:
As described for example 9, 6-[5-methyl-3-(1-methyl-butyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.63 mmol), instead of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, was converted using isopropylamine instead of rac-2-amino-1-propanol, to the title compound (40 mg, 17%) which was obtained as a colourless oil after purification by chromatography (silica, 0 to 5% methanol in dichloromethane). MS: m/e=346.4 [M+H]
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][CH:37]4[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH2:42]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)cc1F
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c12) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow foam.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([S:7]([N:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[CH3:11])(=[O:9])=[O:8])[N:3]=1.[CH3:20][N:21]=[C:22]=[O:23].C(N(CC)CC)C>O1CCCC1>[NH2:1][C:2]1[N:6]([C:22](=[O:23])[NH:21][CH3:20])[N:5]=[C:4]([S:7]([N:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[CH3:11])(=[O:9])=[O:8])[N:3]=1
Reactant: CN=C=O
Reactant: CN(c1c(Cl)cccc1Cl)S(=O)(=O)c1n[nH]c(N)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)n1nc(S(=O)(=O)N(C)c2c(Cl)cccc2Cl)nc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.0 g (6.2 mmol) 5-Amino-N-(2,6-dichlorophenyl)-N-methyl-1,2,4-triazole-3-sulphonamide was suspended in 30 ml tetrahydrofuran and treated with 0.5 ml (8.5 mmol) methyl isocyanate and 0.9 ml (6.5 mmol) triethylamine. The mixture was stirred for 3 hours at room temperature and allowed to stand overnight. The solution was concentrated and the residue chromatographed on silica gel using a mixture of hexane and ethyl acetate.
Reaction SMILES: [CH3:1][S:2]([CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH2:27][CH3:28])[NH:16][C:17](=[O:18])[C:11]2=[CH:10][N:9]=1)=[O:3].ClC1C=C(C=CC=1)C(OO)=[O:34]>ClCCl>[CH3:1][S:2]([CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH2:27][CH3:28])[NH:16][C:17](=[O:18])[C:11]2=[CH:10][N:9]=1)(=[O:34])=[O:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCOc1ccccc1-c1nc2nc(NCCCS(C)=O)ncc2c(=O)[nH]1
Solvent: ClCCl
Product: CCCOc1ccccc1-c1nc2nc(NCCCS(C)(=O)=O)ncc2c(=O)[nH]1

Procedure:
A solution of 7-(3-methylsulphinylpropylamino)-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.80 g) and m-chloroperoxybenzoic acid (0.40 g) in dichloromethane (50 ml) was stirred at ambient temperature for 24 hours. During this time further m-chloroperoxybenzoic acid (about 200 mg) was added on 2 occasions. The solution was washed with dilute aqueous sodium bicarbonate (3×25 ml) and the combined washings back-extracted with a little dichloromethane. The combined organic layer was washed with water and then brine, dried (magnesium sulphate) and evaporated under reduced pressure to yield a residue. This was recrystallised three times from methanol to yield the title compound, 0.51 g, m.p. 222°-3° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[N:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>CCOC(C)=O>[Br:11][C:8]1[CH:9]=[CH:10][C:2]([O:12][C:13]2[CH:18]=[N:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Br)ccc1Br
Reactant: Oc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(Br)ccc1Oc1ccc(Cl)nc1
Temperature: 105 °C
Reaction time: 0.33 h
Yield: 87.7 %

Procedure:
A mixture of 2,5-dibromobenzoic acid (1244 g, 4.44 mol), 5-hydroxy-2-chloropyridine (663.3 g, 5.12 mol) and cesium carbonate (2893.3 g, 8.88 mol) was stirred for 20 minutes under a nitrogen atmosphere. To this slurry were added copper (I) trifluoromethanesulfonate toluene complex (59.7 g, 0.115 mol), toluene (9 L) and EtOAc (39 mL). The resulting suspension was heated to 105° C. and stirred for 2 h before being cooled to RT. The toluene was decanted, and water (8 L) and EtOAc (8 L) were added. The resulting mixture was stirred until the solid was completely dissolved. The EtOAc layer was separated and the pH of the aqueous layer was adjusted to pH 2˜3 with 6N HCl. The aqueous layer was extracted with EtOAc (3×5 L). The combined organic layers were dried over Na2SO4, filtered and concentrated to give 1.28 Kg of 5-bromo-2-(6-chloropyridin-3-yloxy)benzoic acid as brown solid. This material was used in next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:26])[C:15]([NH:17][C@@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])=[O:16])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:26])[C:15](=[O:16])[NH:17][C@@H:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH3:19])=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(=O)N[C@H](C)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C(=O)N[C@H](C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using 2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-hydroxy-N-((R)-1-phenyl-ethyl)-acetamide and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](SC)=[CH:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[CH3:17][NH:18][CH3:19]>CCO>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8]([N:18]([CH3:19])[CH3:17])=[CH:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CSC(=C[N+](=O)[O-])NCc1ccc(Cl)cc1
Reactant: CNC
Solvent: CCO
Product: CN(C)C(=C[N+](=O)[O-])NCc1ccc(Cl)cc1
Yield: 47.3 %

Procedure:
In 100 ml of EtOH was dissolved 2.59 g (0.01 mole) of 1-(4-chlorobenzyl)amino-1-methylthio-2-nitroethylene with heating. Then, with refluxing and stirring, a solution of 2.25 g of 50% aqueous dimethylamine solution in 10 ml of EtOH was added dropwise over a period of 35 minutes. After completion of dropwise addition, the mixture was further stirred and refluxed for 2.5 hours. The solvent was then distilled off and the residue was diluted with ether and triturated, whereupon crystals separated. After addition of EtOH and ether (about 1:5), the crystals were collected by filtration, washed with ether and dried. The procedure gave 1.21 g of the title compound as white crystals.