Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:19][C:20]1[CH:25]=[C:24]([CH:26]=O)[CH:23]=[C:22]([CH3:28])[N:21]=1.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:19][C:20]1[CH:25]=[C:24]([C:26]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[C:8]([CH2:11][CH2:12][N:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)[CH:7]=3)[N:1]=2)[CH:23]=[C:22]([CH3:28])[N:21]=1
Reactant: Cc1cc(C=O)cc(C)n1
Reactant: NC(=O)c1cc(CCN2CCOCC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3ccc(CCN4CCOCC4)cc3c(=O)[nH]2)cc(C)n1
Temperature: 120 °C

Procedure:
To a solution of 2-amino-5-(2-morpholin-4-yl-ethyl)-benzamide (0.18 g, 0.70 mmol) in N,N-dimethyl acetamide (7 mL) under nitrogen atmosphere were added 2,6-dimethyl-pyridine-4-carbaldehyde (0.10 g, 0.70 mmol), sodium hydrogensulfite (58.5 wt %, 0.15 g, 1.40 mmol) and p-toluenesulfonic acid (0.34 g, 1.80 mmol). The resulting mixture was heated at 120° C. for 16 hours, then cooled to room temperature. The solvent was removed under reduced pressure, and the residue was diluted with methylene chloride (100 mL). The organic phase was washed with saturated aqueous sodium bicarbonate solution, then water, and dried over anhydrous sodium sulfate. The crude orange solid (0.21 g) was purified by column chromatography (silica gel 230-400 mesh; 95:5 methylene chloride and MeOH as eluent) to give the title compound as a yellow solid. Yield: 0.11 g (42%). MP 248.5-249.3° C. 1H NMR (400 MHz, CDCl3): δ 11.6 (s, 1H), 8.18 (s, 1H), 7.87-7.76 (m, 3H), 7.76-7.65 (m, 1H), 3.76 (t, J=4.49 Hz, 4H), 2.99 (t, J=8.01 Hz, 4H), 2.71 (s, 6H), 2.75-2.65 (m, 2H), 2.56 (br s, 4H). MS (ES+) m/z: 363.16 (M+1).
Reaction SMILES: CC([O-])C.CC([O-])C.CC([O-])C.[Al+3].[CH2:14]([C:16]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])([CH:19]=[CH:20][CH2:21][CH3:22])[CH:17]=[O:18])[CH3:15].CC(C)=O>C(O)(C)C>[CH2:14]([C:16]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])([CH:19]=[CH:20][CH2:21][CH3:22])[CH2:17][OH:18])[CH3:15]
Reactant: CCC=CC(C=O)(CC)CC=C(C)C
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CCC=CC(CC)(CO)CC=C(C)C

Procedure:
Into a 2 liter four-neck flask, provided with stirrer, column, dropping funnel, and thermometer, 0.5 moles of aluminum isopropylate and 1 liter of dry isopropanol are first introduced. To the boiling mixture, a solution of 1 mole 2-ethyl-2-prenyl-3-hexenal, dissolved in 200 ml of dry isopropanol were added drop by drop. At all times, the reaction mixture was kept boiling to the extent that the acetone being formed could be withdrawn by the column. When in the distillate acetone could no longer be detected, the isopropanol was distilled off. Finally, the residue was poured into 250 ml of 20% hydrochloric acid, the phases were separate, and the organic phase was dried with calcium chloride. The desired product was then distilled over a Vigreux column.
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH:3](O)[OH:4].S(O)(O)(=O)=O.[NH2:13][C:14]1[N:15]=[C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH2:29][CH2:30][CH3:31])[NH:17][C:18](=[O:21])[C:19]=1[NH2:20]>CO>[CH2:29]([O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:16]1[NH:17][C:18](=[O:21])[C:19]2[NH:20][C:3](=[O:4])[CH:2]=[N:13][C:14]=2[N:15]=1)[CH2:30][CH3:31]
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCCOc1ccccc1-c1nc2ncc(=O)[nH]c2c(=O)[nH]1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
A solution of chloral hydrate (1.74 g) in 50% aqueous methanol (10 ml) was added over 10 minutes to a stirred solution of 4,5-diamino-2-(2-propoxyphenyl)pyrimidin-6-one sulphate (1.89 g) in 50% aqueous methanol (60 ml) at 80° C. and the reaction mixture was stirred at 80° C. for 1.5 hours. The cooled reaction mixture was filtered to remove an orange brown solid which was discarded. On standing overnight the filtrate afforded a crude solid product (0.96 g) which was collected and washed with dilute aqueous potassium bicarbonate and water. The crude product together with another sample (0.20 g) similarly prepared was eluted from a silica column with chloroform. The combined fractions containing product were evaporated under reduced pressure to afford a solid (0.54 g) which was recrystallised from acetonitrile to afford the title compound, 0.39 g, m.p. 232°-233.5° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O-:9])=[O:8].[Li+].[OH-].Cl>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8]
Reactant: O=C([O-])c1ccccn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccccn1
Temperature: 60 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
To a solution of methyl 3-amino-6-(2-fluoro-5-isopropylcabamoyl)phenyl)picolinate (1.0 equiv) in THF (0.5M), was added 1M LiOH (4.0 equiv). After stirring for 4 hours at 60° C., 1 N HCl (4.0 equiv.) was added and the THF was removed in vacuo. The resulting solid was filtered and rinsed with cold H2O (3×20 mL) to yield 3-amino-6-(2-fluoro-5-isopropylcabamoyl)phenyl)picolinic acid (98%). LCMS (m/z): 318.1 (MH+); LC Rt=2.4 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].[F:14][C:15]([F:20])([F:19])[CH2:16][CH2:17]I>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][N:8]([CH2:17][CH2:16][C:15]([F:20])([F:19])[F:14])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Reactant: FC(F)(F)CCI
Product: CCOC(=O)c1nn(CCC(F)(F)F)cc1[N+](=O)[O-]
Yield: 15 %

Procedure:
The product was obtained according to the method described in example 4, step 2 starting from 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester and 1,1,1-trifluoro-3-iodo-propane as a mixture of regioisomers which were separated by silica gel chromatography using a heptane/ethyl acetate gradient to yield 141 mg (31%) of the desired regioisomer and 68 mg (15%) of 4-nitro-1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboxylic acid ethyl ester.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=O.[CH3:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1.Br[Si](C)(C)C>CN(C=O)C>[O:14]1[CH2:13][CH2:12][N:11]([C:10]2[C:5]3[N:6]([C:17]([CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)=[C:3](/[CH:1]=[CH:31]/[C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:16][CH2:15]1
Reactant: Cc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c(C=O)nc3c(N4CCOCC4)ccnn23)CC1
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)CC1
Temperature: 25 °C

Procedure:
A solution of compound 41c (0.40 g, 0.96 mmol), 2-methylquinoline (0.17 g, 1.2 mmol) and bromotrimethylsilane (0.32 g, 2.9 mmol) in DMF (4 mL) was stirred at 80° C. for 5 h and allowed to cool to rt. The solids formed were collected by filtration, and washed with methanol (50 mL) to obtain compound 48a as a brown solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C31H36N6O3: 541.3 (M+H). Found: 541.2.
Reaction SMILES: [N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:15](=[O:25])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH:23]=O)[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.Cl.[NH2:33]O>CN1CCCC1=O>[N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:15](=[O:25])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[C:23]#[N:33])[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(C=O)c2c(=O)n1-c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CN1CCCC1=O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(C#N)c2c(=O)n1-c1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 28.6 %

Procedure:
To a solution of (S)-3-(1-((9H-purin-6-yl)amino)ethyl)-1-oxo-2-phenyl-1,2-dihydroisoquinoline-8-carbaldehyde (15) (50 mg, 0.12 mmol) in anhydrous 1-methyl-2-pyrrolidinone (3 mL), hydroxylamine hydrochloride (17 mg, 0.24 mmol) was added and the resulting mixture was stirred at 120° C. for 16 h. The mixture was allowed to cool to RT, partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO (silica gel cartridge, 0-10% MeOH-DCM) to afford the product, (S)-3-(1-((9H-purin-6-yl)amino)ethyl)-1-oxo-2-phenyl-1,2-dihydroisoquinoline-8-carbonitrile (16) (14 mg, 28% yield) as a while solid. ESI-MS m/z: 408.2 [M+H]+.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([Br:12])=[CH:14][CH:15]=1)[CH2:4]2
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)cc1

Procedure:
Prepared by a method analogous to that described for the preparation of Intermediate 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and 4-bromobenzoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent. The compound was then dissolved in tetrahydrofuran, excess hydrogen chloride (1M solution in diethyl ether) was added, and the solution was evaporated and then recrystallised from methanol/t-butyl methyl ether to give the hydrochloride salt of the title compound as a colourless solid; MS (ES+) 309, 311 (MH+).
Reaction SMILES: [CH2:1]([C:3]1([N:9]2[CH2:18][C:17]3=[CH:19][NH:20][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][N:14]=4)[C:10]2=[O:21])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.[C:29]([CH2:31][C:32](ON1C(=O)CCC1=O)=[O:33])#[N:30]>CCO>[CH2:1]([C:3]1([N:9]2[CH2:18][C:17]3=[CH:19][NH:20][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][N:14]=4)[C:10]2=[O:21])[CH2:8][CH2:7][N:6]([C:32](=[O:33])[CH2:31][C:29]#[N:30])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(N2Cc3c[nH]c4nccc(c34)C2=O)CCNCC1
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCC1(N2Cc3c[nH]c4nccc(c34)C2=O)CCN(C(=O)CC#N)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.7 %

Procedure:
4-(4-Ethylpiperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one (25 mg, 0.088 mmol) and triethylamine (0.037 mL, 0.264 mmol) were dissolved in EtOH (3 mL) and cooled to 0° C. and allowed to stir for 10 min. Then 2,5-dioxopyrrolidin-1-yl 2-cyanoacetate (19 mg, 0.106 mmol) dissolved in EtOH (1 mL) was added dropwise and the mixture was allowed to stir for 30 min at 0° C. The solution was concentrated in vacuo and purified via preparative HPLC 10% to 50% B in A and gave 16 mg of the title compound as its TFA salt. 1H NMR (400 MHz, CD3OD) δ 7.03 (m, 1H), 6.86 (m, 1H), 4.53 (d, 2H, J=2.0 Hz), 3.08-3.11 (m, 2H), 2.93-2.94 (m, 2H), 2.72-2.73 (m, 2H), 2.04-2.09 (m, 1H), 1.91-1.94 (m, 1H), 1.36-1.72 (m, 4H), 0.35 (t, 3H, J=7.6 Hz). [M+H] found 352.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][S:21][C:3]=12.[CH:22]1([S:26](Cl)(=[O:28])=[O:27])[CH2:25][CH2:24][CH2:23]1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:26]([CH:22]2[CH2:25][CH2:24][CH2:23]2)(=[O:28])=[O:27])=[C:3]2[S:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: O=S(=O)(Cl)C1CCC1
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCS2
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CCC2)c2n(c1=O)CCS2
Yield: 14 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 19A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (I-19f: 0.1 g, 0.23 mmol) in pyridine (2 mL) was reacted with cyclobutanesulfonyl chloride (0.04 g, 0.20 mmol) to afford the crude product. Purification by preparative HPLC afforded 15 mg of the product (12% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:33])([C@H:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28](COCC)[N:27]=[N:26][CH:25]=2)=[CH:20][CH:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.Cl>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:33])([C@H:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[N:27][NH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CCOCn1nncc1-c1ccc([C@H](C)[C@](O)(Cn2cncn2)c2ccc(F)cc2F)cc1
Agent: Cl
Solvent: CCO
Product: C[C@@H](c1ccc(-c2c[nH]nn2)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 8.5 %

Procedure:
A solution of (2R,3S)-2-(2,4-difluorophenyl)-3-(4-[1-ethoxymethyl-1,2,3-triazol-5-yl]phenyl)-1-(1,2,4-triazol-1-yl)butan-2-ol (5.2 g, 0.11 mol-see Example 25) in ethanol (50 ml) was treated with dilute hydrochloric acid (2N, 12 ml) and the mixture was heated under reflux for one hour. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in water (50 ml) and the mixture was neutralized by addition of solid sodium carbonate and was extracted with ethyl acetate (2×100 ml). The combined extracts were dried (MgSO4) and evaporated under reduced pressure to yield a colourless foam. The crude product was purified by column chromatography on silica by elution with ethyl acetate/diethylamine (95:5) followed by ethyl acetate/methanol (90:10 then 80:20). Fractions containing the desired product were combined and evaporated under reduced pressure to yield the title compound as a colourless foam (3.7 g, 82%), [α]D25 =-63.8°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[C:6]([N:8]([CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:7].[CH:25]12[O:31][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30]2>>[OH:31][C@@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[N:19]1[CH2:18][CH2:17][CH:16]([N:8]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[C:6](=[O:7])[C:5]2[CH:22]=[CH:23][CH:24]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:21][CH2:20]1
Reactant: C1CCC2OC2C1
Reactant: COc1cccc(C(=O)N(c2ccc(C)cc2)C2CCNCC2)c1
Product: COc1cccc(C(=O)N(c2ccc(C)cc2)C2CCN([C@@H]3CCCC[C@H]3O)CC2)c1

Procedure:
The title compound, MS (ISP): m/e=499.0 (M+H+), was prepared as for example 141, steps (A) to (F). Step (B) was performed using 3-methoxybenzoyl chloride, and yielded 4-[(3-methoxy-benzoyl)-p-tolyl-amino]-piperidine-1-carboxylic acid tert-butyl ester. This was then deprotected to 3-methoxy-N-piperidin-4-yl-N-p-tolyl-benzamide (step C), and reacted with cyclohexene oxide to give (+/−)-N-[trans-1-(2-hydroxy-cyclohexyl)-piperidin-4-yl]-3-methoxy-N-p-tolyl-benzamide [step (D)]. Oxidation to (+/−)-3-methoxy-N-[1-(2-oxo-cyclohexyl)-piperidin-4-yl]-N-p-tolyl-benzamidein step (E) and reaction with phenyl lithium [step (F)] led to the title compound of the example.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[C:4]([O:3][C:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[CH2:9]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCOCC2)C1
Yield: 62 %

Procedure:
The subtitle compound was prepared by the method of Example 5(e) with (R/S)-1-Boc-pyrrolidine-3-carboxylic acid [MacLeod et al J. Med. Chem., 33, 2052 (1990)] and morpholine. The subtitle compound (62%) was obtained as an oil. Rf 0.69 (CH2Cl2 /MeOH 95/5, v/v). MS m/z 285 (MH+).
Reaction SMILES: Br[C:2]1[S:3][C:4]([Cl:7])=[CH:5][CH:6]=1.OB(O)[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:7][C:4]1[S:3][CH:2]=[CH:6][C:5]=1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Clc1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(O)c1ccc(-c2ccsc2Cl)cc1
Temperature: 75 °C
Reaction time: 0.08 h

Procedure:
Solid Pd(PPh3)4 (11.0 mg, 0.01 mmol) was treated with a room temperature solution of 2-bromo-5-chlorothiophene (143 mg, 0.72 mmol) in DME (4 mL), stirred for 5 minutes, treated with a solution of 4-(dihydroxyboryl)benzoic acid (100 mg, 0.60 mmol) in DME (2 mL), and stirred for 5 minutes. The mixture was treated with 2M Na2CO3 (1.5 mL, 3.0 mmol), heated to 75° C., stirred for 18 hours, cooled to room temperature, filtered, triturated with water (3 mL), and concentrated. The concentrate was treated with boiling water (4 mL), filtered through celite, cooled to room temperature, adjusted to pH<7 with HCl, and filtered to provide the desired product. MS (APCI(+)) m/e 239 (M+H)+.
Reaction SMILES: [CH3:1][SH:2].Br[C:4]1[C:14]([O:15][CH3:16])=[C:13]([Br:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:17][C:13]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([S:2][CH3:1])[C:14]=1[O:15][CH3:16]
Reactant: CCOC(=O)c1ccc(Br)c(OC)c1Br
Reactant: CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(Br)c(OC)c1SC

Procedure:
A solution of methanethiol (47 ml) in dimethyl formamide was added to a mixture of ethyl 2,4-dibromo-3-methoxybenzoate (105 g) and potassium carbonate (131 g) in dimethyl formamide and the resultant suspension was stirred at room temperature overnight. Water was added and the mixture was extracted into ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by column chromatography eluted with a mixture of ethyl acetate and cyclohexane to give as the minor component ethyl 4-bromo-3-methoxy-2-(methylsulphenyl)benzoate (4.5 g) as a white solid, NMR (CDCl3) 1.5(t,3H), 2.6(s,3H), 4.05(s,3H), 4.5(q,2H), 7.35 (m,2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][NH:21][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:18][CH:19]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(CN)cc2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(CNS(C)(=O)=O)cc2)n1
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
To a solution of [6-(4-aminomethyl-phenyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (5.7 g 19 mmol) and Et3N (2.88 g, 29 mmol) in dichloromethane (50 mL) was added dropwise MsCl (2.7 g, 19 mmol) at 0° C. The reaction mixture was stirred at this temperature for 30 min, and then washed with water and brine, dried over Na2SO4 and concentrated to dryness. The residue was recrystallized with DCM/Petroleum Ether (1:3) to give {6-[4-(methanesulfonylamino-methyl)-phenyl]-pyridin-2-yl}carbamic acid tert-butyl ester (4.0 g, 44% over two steps). 1H NMR (300 MHz, CDCl3) δ 7.90-7.97 (m, 3 H), 7.75 (t, J=8.4, 8.4 Hz, 1 H), 7.54-7.59 (m, 1 H), 7.38-7.44 (m, 3 H), 4.73 (br, 1 H), 4.37 (d, J=6.0 Hz, 2 H), 2.90 (s, 3 H), 1.54 (s, 9 H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f19) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [N+:1]([C:4]([C:15](=O)[CH3:16])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)([O-:3])=[O:2].[NH2:18][C:19]([CH3:24])=[CH:20][N+:21]([O-:23])=[O:22]>C(O)C>[CH3:16][C:15]1[NH:18][C:19]([CH3:24])=[C:20]([N+:21]([O-:23])=[O:22])[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=2)[C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CC(N)=C[N+](=O)[O-]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)[N+](=O)[O-]
Solvent: CCO
Product: CC1=C([N+](=O)[O-])C(c2cccc([N+](=O)[O-])c2)C([N+](=O)[O-])=C(C)N1

Procedure:
23.6 g (0.1 mol) of 2-nitro-1-(3nitrophenyl)-but-1-ene-3-one and 10.2 g (0.1 mol) of 2-amino-1-nitro-prop-1-ene in 150 ml of ethanol were heated under reflux for 12 hours. After the mixture had cooled, the solvent was distilled off in vacuo, and the oily residue was taken up in chloroform, and was chromatographed on a silica gel column, using chloroform with the addition of methanol. The product formed yellow crystals of melting point 237°-240° C. (decomposition) in isopropanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:13])=[CH:8][CH2:7][CH2:6]2.P(Cl)(Cl)(Cl)=O.[C:19]([O-])(=[O:21])C.[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:13])=[C:8]([CH:19]=[O:21])[CH2:7][CH2:6]2
Reactant: CC(=O)[O-]
Reactant: COc1ccc2c(c1)CCC=C2C
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)CCC(C=O)=C2C
Temperature: 72.5 °C
Reaction time: 3 h
Yield: 43.5 %

Procedure:
To a solution of Compound B (0.44 g, 2.5 mmole) in dry dimethylfomamide (1.3 ml, 16.8 mmole) at ice cooling and stirring under argon atmosphere, phosphorus oxychloride (0.62 ml, 6.65 mmole) was added drop-by-drop in 2 minutes. The reaction mixture was stirred in an oil bath of 70-75° C. for 3 hours. After cooling in an ice bath, ice (6 g) was added, then sodium acetate (anhydrous, 3.7 g) was added, and the mixture (pH 6) was warmed in an oil bath at 70-75° C. for 15 minutes. After cooling, it was extracted with ether (1×10 ml and 3×5 ml), the combined organic solutions were washed with water (3×3 ml), dried (magnesium sulfate), decolorized (with activated carbon), and evaporated. The residue (0.33 g) was recrystallized from cyclohexane (2 ml) and dried over potassium hydroxide in a vacuum giving the pure product 6-Methoxy-1-methyl-3,4-dihydro-2-naphthaldehyde (Compound C, 0.22 g, 44%) as light brown crystals, mp. 70-72° C.