Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](OC(OCC)OCC)C.[CH3:11][O:12][C:13]1[N:18]=[C:17]([NH:19][CH2:20][C:21]2[CH:31]=[CH:30][C:24]3[N:25]=[C:26]([S:28][CH3:29])[S:27][C:23]=3[CH:22]=2)[C:16]([NH2:32])=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[N:18]=[C:17]2[N:19]([CH2:20][C:21]3[CH:31]=[CH:30][C:24]4[N:25]=[C:26]([S:28][CH3:29])[S:27][C:23]=4[CH:22]=3)[CH:1]=[N:32][C:16]2=[CH:15][CH:14]=1
Reactant: CCOC(OCC)OCC
Reactant: COc1ccc(N)c(NCc2ccc3nc(SC)sc3c2)n1
Product: COc1ccc2ncn(Cc3ccc4nc(SC)sc4c3)c2n1
Temperature: 25 °C
Yield: 53 %

Procedure:
To a solution of triethoxymethane (5 mL) was added 6-methoxy-N2-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamine (332 mg, 1.0 mmol) from Step 6 of this Example at rt. The reaction mixture was heated under reflux overnight. After cooling to rt, the mixture was concentrated under reduced pressure. The crude product was purified on a silica gel column using a mixture of EtOAc-CH2Cl2 (0 to 100%, v/v) as eluent to give 6-((5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole as a brown solid (180 mg, 53%). 1H NMR (300 MHz, CDCl3) δ 7.95 (d, J=8.7 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.70 (d, J=1.1 Hz, 1H), 7.41 (dd, J=1.7, 8.3 Hz, 1H), 6.71 (d, J=8.7 Hz, 1H), 5.47 (s, 2H), 3.99 (s, 3H), 2.78 (s, 3H). LCMS (ESI) m/z 343 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]([CH3:20])[C:8]([NH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)=[O:9].[NH2:21][C:22]1[C:27]([NH:28]C(=O)OCC2C=CC=CC=2)=[CH:26][CH:25]=[C:24]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:23]=1>>[NH2:28][C:27]1[C:22]([NH:21][C:15](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[CH:7]([N:3]3[CH2:4][CH2:5][CH2:6][C:2]3=[O:1])[CH3:20])=[CH:19][CH:18]=2)=[N:23][C:24]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:25][CH:26]=1
Reactant: CC(C(=O)Nc1ccc(C(=O)O)cc1)N1CCCC1=O
Reactant: Nc1nc(-c2ccccc2)ccc1NC(=O)OCc1ccccc1
Product: CC(C(=O)Nc1ccc(C(=O)Nc2nc(-c3ccccc3)ccc2N)cc1)N1CCCC1=O

Procedure:
Similar procedure from Example 2 was followed to obtain benzyl 2-(4-(2-(2-oxopyrrolidin-1-yl)propanamido)benzamido)-6-phenylpyridin-3-ylcarbamate using 4-(2-(2-oxopyrrolidin-1-yl)propanamido)benzoic acid and benzyl 2-amino-6-phenylpyridin-3-ylcarbamate. The Cbz group was then deprotected under standard hydrogenation conditions to give the title compound. C25H25N5O3 444.0 (M+1). 1H NMR (400 MHz, DMSO-d6): δ 10.29 (s, 1H); 10.25 (s, 1H); 8.01 (d, J=8.8 Hz, 2H); 7.92 (d, J=8.8 Hz, 2H); 7.71 (d, J=8.4 Hz, 2H); 7.65 (d, J=8.4 Hz, 1H); 7.38-7.35 (m, 2H); 7.27-7.22 (m, 2H); 5.11 (s, 2H); 4.70 (q, J=7.2 Hz, 1H); 3.55 (m, 1H); 3.44 (m, 1H); 2.26-2.23 (m, 2H); 1.97-1.91 (m, 2H); 1.36 (d, J=7.2 Hz, 3H).
Reaction SMILES: C([Mg]Cl)CCC.C(NC(C)C)(C)C.[C:14]1([S:20]([N:23]2[C:31]3[C:26](=[C:27]([N:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]4)[CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[I:45]I>C1COCC1>[I:45][C:24]1[N:23]([S:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:22])=[O:21])[C:31]2[C:26]([CH:25]=1)=[C:27]([N:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1)[CH:28]=[CH:29][CH:30]=2
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: CCCC[Mg]Cl
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2cc(I)n3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of butylmagnesium chloride (1 mL, Immol, 2.0 M in ether) and di-isopropyl amine (0.279 mL, 2 mmol) in dry THF (5 mL) was stirred for 4 h under inert atmosphere at room temperature. A solution of tert-butyl 4-[1-(phenylsulfonyl)-1H-indol-4-yl]-1-piperazinecarboxylate (220 mg, 0.5 mmol) in THF (2 mL) was added slowly and the resulting mixture stirred for 2 h at room temperature. A solution of iodine (380 mg, 2.2 mmol) in THF (2 mL) was added dropwise and the mixture was stirred overnight. After evaporation of the solvent in vacuo, the residue was treated with an aqueous solution of NH4Cl (10 mL). The mixture was extracted with CH2Cl2 (3×10 mL) and the combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2) using CH2Cl2 as eluent to give 100 mg (35%).1H NMR (500 MHz, CDCl3) δ 8.05–7.80 (m, 3 H), 7.60–7.35 (m, 3 H), 7.19 (t, J=8 Hz, 1 H), 6.98 (s, 1 H), 6.72 (d, J=8 Hz, 1 H), 3.62 (m, 4 H), 3.05 (m, 4 H), 1.47 (m, 9 H); MS (ESI+) for m/z 568 (M+H)+.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:23][C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10]
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNc1nc(Cc2ccsc2)[nH]c(=O)c1C#N

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 521 mg (3.80 mmol) of 2-methoxybenzylamine to give 62 mg (46% of theory) of the title compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[C:8]([CH:14]([CH3:16])[CH3:15])[CH:7]=1>C(#N)C.O>[Cl:5][C:6]1[CH:7]=[C:8]([CH:14]([CH3:15])[CH3:16])[C:9]([OH:13])=[C:10]([N+:1]([O-:4])=[O:2])[C:11]=1[CH3:12]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(O)c(C(C)C)cc1Cl
Solvent: O
Solvent: CC#N
Product: Cc1c(Cl)cc(C(C)C)c(O)c1[N+](=O)[O-]
Reaction time: 0.83 h
Yield: 81.9 %

Procedure:
Acetyl nitrate obtained by mixing acetyl anhydride (1.12 g, 11 mmol) with fuming nitric acid (693 mg, 11 mmol) at 0° C. was dropped into a solution of 4-chloro-2-isopropyl-5-methylphenol (1.84 g, 10 mmol) in acetonitrile (20 ml) at 0° C. followed by stirring for 50 minutes. The reaction solution was diluted with water and extracted with ether. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (80 g of silica gel; developing solvent, hexane:methylene chloride=30:1→10:1) to provide 1.88 g (yield 83%) of 4-chloro-6-isopropyl-3-methyl-2-nitrophenol as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:15])([CH3:14])[CH2:4][CH2:5][CH:6]1[CH2:11][C:10]([CH3:12])=[CH:9][C:8](=[O:13])[CH2:7]1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]([CH3:14])([CH3:15])[CH2:4][CH2:5][CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][C:8](=[O:13])[CH2:7]1
Reactant: [H][H]
Reactant: COC(C)(C)CCC1CC(=O)C=C(C)C1
Agent: [Pd]
Solvent: CO
Product: COC(C)(C)CCC1CC(=O)CC(C)C1

Procedure:
A solution of 3-(3-methoxy-3-methylbut-1-yl)-5-methylcyclohex-5-en-1-one (30.0 g, 0.14 mol) in methanol (150 mL) was placed in a thick walled bottle. Palladium on charcoal (5%, 2.0 g) was added and the mixture was shaken under 53.5 psi of hydrogen. When the theoretical amount of hydrogen had been consumed, workup yielded 3-(3-methoxy-3-methylbut-1-yl)-5-methylcyclohexan-1-one as a mixture of two diastereoisomers bp0.5 104°-107° C. (27.6 g, ratio 69:93.1); NMR(CDCl3)δ1.0(d,3H), 1.1(s,6H), 1.3-1.5(m,6H), 1.6-2.0(m,4H), 2.2-2.4(m,2H),3.1(s,3H). IR(neat) 2970, 2925, 1720, 1360, 1090 cm-1 ; MS(m/e) 41, 73, 124, 147, 165, 180, 197.
Reaction SMILES: O=[C:2]1[NH:8][C:7]2=[CH:9][CH2:10][S:11][C:6]2=[CH:5][N:4]2[CH:12]=[CH:13][CH:14]=[C:3]12.CO>O1CCCC1>[S:11]1[C:6]2[CH2:5][N:4]3[CH:12]=[CH:13][CH:14]=[C:3]3[CH2:2][NH:8][C:7]=2[CH:9]=[CH:10]1
Reactant: O=C1NC2=CCSC2=Cn2cccc21
Solvent: C1CCOC1
Solvent: CO
Product: c1cc2n(c1)Cc1sccc1NC2
Temperature: 25 °C

Procedure:
To a suspension of 7.0 g of 5-oxo-4,5-dihydropyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine in 25 ml of anhydrous tetrahydrofuran is added 9 ml of 10M boranedimethylsulfide in tetrahydrofuran. The mixture is refluxed for 6 hours. The solution is cooled to room temperature and 25 ml of methanol added dropwise. The volatiles are removed under vacuum. To the residue is added 100 ml of 2N NaOH. The mixture is refluxed 5 hours and filtered. The solid is extracted with dichloromethane and the extract is washed with 2N citric acid, water and dried (Na2SO4). The solvent is removed to give a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13]>CS(C)=O>[Cl:8][C:4]1[N+:3]([O-:9])=[C:2]([NH:14][CH2:10][CH2:11][CH2:12][CH3:13])[CH:7]=[CH:6][CH:5]=1
Reactant: [O-][n+]1c(Cl)cccc1Cl
Reactant: CCCCN
Solvent: CS(C)=O
Product: CCCCNc1cccc(Cl)[n+]1[O-]
Temperature: 120 °C

Procedure:
To a solution consisting of 9.9 grams (0.055 mole) of 2,6-dichloropyridine-N-oxide in 50 milliliters of dimethylsulfoxide was slowly added 8.4 grams (0.115 mole) of n-butylamine. The temperature of the mixture was 75°C. at the start of the reaction and was allowed to increase to 120°C. After a total reaction time of ~21/2 hours, 3/4 of the dimethyl sulfoxide was removed by evaporation and the reaction mixture poured into cold water. The solid 6-chloro-2-(n-butylamino)pyridine-N-oxide product which precipitated was recovered by filtration in the yield of 6.0 grams. The product melted was 103°-104°C. and was found upon analysis to have carbon, hydrogen, chlorine and contents of 54.1, 6.9, 17.9 and 13.8 percent, respectively, as compared with the theoretical contents of 54.0, 6.5, 17.8 and 14.0 percent, respectively, calculated for the above named compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH:26]1[CH:31]=[C:30]([OH:32])[CH:29]=[C:28]([CH:33]([OH:36])[CH2:34][NH2:35])[CH:27]=1>>[OH:36][CH:33]([C:28]1[CH:27]=[CH:26][CH:31]=[C:30]([OH:32])[CH:29]=1)[CH2:34][NH:35][CH:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[CH:14][C:13]([NH:12][S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:10])=[O:11])=[CH:18][CH:17]=2)[CH2:24][CH2:23]1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NCC(O)c1cccc(O)c1
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NCC(O)c4cccc(O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from 4-methoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 218) and DL-norphenylephrine according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.25–1.60 (m, 2 H), 2.00–2.15 (m, 2 H), 2.50–3.10 (m, 5 H), 3.60–3.70 (m, 2 H), 3.79 (s, 3 H), 4.80–4.90 (m, 1 H), 6.05 (brs, 1 H), 6.70–6.80 (m, 1 H), 6.80–6.85 (m, 4 H), 6.90 (d, J=9.0 Hz, 2 H), 7.02 (d, J=9.0 Hz, 2 H), 7.16 (t, J=7.7 Hz, 1 H), 7.60 (d, J=9.0 Hz, 2 H), 9.45 (s, 1 H), 9.70 (s, 1 H); MS (ES) m/z: 498.5 (MH+); HRMS Calcd. for C26H31N3O5S(M+): 497.1984. Found: 497.1961.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[N:5]=1)[CH3:2].S(OC)(O[CH3:18])(=O)=O>[OH-].[Na+]>[CH2:12]([N:3]([CH2:1][CH3:2])[C:4]1[N:5]=[C:6]([O:11][CH3:18])[CH:7]=[C:8]([OH:10])[N:9]=1)[CH3:13]
Reactant: COS(=O)(=O)OC
Reactant: CCN(CC)c1nc(O)cc(O)n1
Agent: [Na+]
Agent: [OH-]
Product: CCN(CC)c1nc(O)cc(OC)n1

Procedure:
500 cc of sodium hydroxide solution 1N are added while stirring to 91.5 g (0.5 mol) of 2-diethylamino-4,6-dihydroxy-pyrimidine. The solution is stirred at 50° for a short period and then cooled to 20° . 63 g (0.5 mol) of dimethyl sulphate are added dropwise, over the course of 1 hour, to the clear solution; by further addition of 1N sodium hydroxide solution the pH value is kept between 7.5 and 8. A total of approximately 100 cc of 1N sodium hydroxide solution is additionally required. The mixture is stirred for a further 5 hours at room temperature and the precipitated crystals are filtered off at 5°; then they are washed with water. The crystalline product is subsequently triturated with 1500 cc of carbon tetrachloride by means of a vibration mixer. The undissolved parts are suction filtered and the carbon tetrachloride solution is then concentrated by evaporation, whereupon crystallization commences; 200 cc of petroleum ether are then added.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]1[CH2:13][NH:12][C@H:11]([C:14]([OH:16])=[O:15])[CH2:10]1.[Br:17][C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.CN(C=O)C>[Br:17][C:18]1[CH:19]=[C:20]([N:12]2[CH2:13][C@@H:9]([CH3:8])[CH2:10][C@H:11]2[C:14]([OH:16])=[O:15])[CH:21]=[CH:22][CH:23]=1
Reactant: Brc1ccc(Br)cc1
Reactant: C[C@@H]1CN[C@H](C(=O)O)C1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: C[C@H]1C[C@@H](C(=O)O)N(c2cccc(Br)c2)C1
Temperature: 95 °C

Procedure:
To (4S)-4-methyl-L-proline trifluoroacetate (2.92 g, 8.17 mmol), 1,4-dibromobenzene (2.9 g, 12.27 mmol), potassium carbonate (3.95 g, 28.6 mmol), and copper iodide (315 mg, 1.64 mmol) was added dry DMF (30 mL) under dry nitrogen. The reaction flask was thoroughly degassed with dry nitrogen and heated at 95° C. for 3 days. Water and hexane were added and the organic phase was separated and discarded (to remove excess 1,4-dibromobenzene). The pH of the aqueous phase was adjusted to 3 with aqueous 10% HCl and the product extracted with EtOAc (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (AcOH/EtOAc/Hex, 0.5/49.5/50) to afford (4S)-1-(3-bromophenyl)-4-methyl-L-proline.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[C:24](=[S:34])(Cl)[O:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1.C(N(CC)CC)C>C1COCC1>[F:23][C:2]([F:1])([F:22])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:21]=[CH:20][C:18]([NH:19][C:24](=[S:34])[O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: Fc1ccc(OC(=S)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1ccc(OC(=S)Nc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)cc1
Reaction time: 2 h
Yield: 16.8 %

Procedure:
Into a 25 mL round-bottomed flask were added 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (200 mg, 0.624 mmol), O-4-fluorophenyl carbonochloridothioate (238 mg, 1.249 mmol), and triethylamine (0.348 mL, 2.498 mmol) in THF (5 mL). The solution was stirred under ambient conditions for 2 h before the solvent was removed under reduced pressure. The crude product was added to a silica gel column and was eluted with EtOAc/hexanes gradient to afford the title compound (50 mg, 0.105 mmol, 17%) as a yellow solid: mp 164-169° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.19-8.04 (m, 6H), 7.97 (br s, 1H), 7.66-7.57 (d, J=8.24 Hz, 2H), 7.33-7.19 (m, 4H); ESIMS m/z 475 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=1)=[O:25].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=2)=[O:25])[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: O=C(CBr)c1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 3.29 g (16.4 mmol) 4-benzyloxy-1H-pyridin-2-one in 16 mL DMF is added 13.3 g (40.9 mmol) cesium carbonate and the mixture is stirred 15 min at RT. Then 3.75 g (16.4 mmol) 2-bromo-1-(4-hydroxymethyl-phenyl)-ethanone (preparation 15a) is added and is stirred 2 h at RT. Water is added, the precipitate is collected, washed with water and dried.
Reaction SMILES: NCCC(O)=O.[C:7]1([CH2:13][CH2:14][O:15][CH2:16][CH:17]=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:19](#[N:23])[CH2:20][C:21]#[N:22]>C(O)C>[C:7]1([CH2:13][CH2:14][O:15][CH2:16][CH:17]=[C:20]([C:19]#[N:23])[C:21]#[N:22])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=CCOCCc1ccccc1
Reactant: N#CCC#N
Agent: NCCC(=O)O
Solvent: CCO
Product: N#CC(C#N)=CCOCCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.6 %

Procedure:
β-Alanine (0.6 g) was added to a solution of [2-phenylethoxy]acetaldehyde (8.0 g) and malononitrile (3.5 g) in ethanol (100 ml). The mixture was stirred at room temperature for 3 hours. The solid was filtered off, washed with fresh ethanol and dried to yield the subtitled compound (5.85 g, 54%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]=[C:9](C3C=CC=CC=3)[O:10][C:3]=12>O1CCCC1.C(O)C.[OH-].[Na+]>[CH3:9][O:10][C:3]1[C:4]([NH2:8])=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccnc2nc(-c3ccccc3)oc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1c(C)ccnc1N
Temperature: 25 °C
Yield: 7.4 %

Procedure:
86 mg of the 7-methyl-2-phenyl[1,3]oxazolo[4,5-b]pyridine [159-1] was dissolved in a mixture solvent of 4 mL of tetrahydrofuran and 4 mL of ethanol, 1.64 mL of an aqueous solution of sodium hydroxide 33% was added thereto, and heated overnight under reflux. After cooling back to room temperature, the reaction solution was concentrated under reduced pressure. To the obtained residue, 5 mL of dichloromethane and 3.4 mL of an aqueous solution of sodium hydroxide 33% were added and stirred. Thereto, 28 μL of methyl iodide and 30.5 μL of Adogen 464 (phase transfer catalyst, Aldrich Corporation) were added, and stirred overnight at room temperature. Water was added, the reaction solution was extracted with chloroform, and the organic layer was washed with phosphate buffer pH 7.0, water, and saturated brine in the subsequent order. The organic layer was dried over anhydrous sodium sulfate, the insolubles were filtered, the filtrate was concentrated under reduced pressure, and the thus obtained residue was purified by preparative thin-layer chromatography, to obtain 4.2 mg of 3-methoxy-4-methylpyridin-2-amine [159-2] as a light brown solid.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[CH:29]=[C:28]([CH3:30])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]4[O:11][CH2:1][O:2][C:3]=4[CH:4]=3)[C:24]3[CH:29]=[C:28]([CH3:30])[S:27][C:25]=3[N:26]=2)=[CH:19][CH:20]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc4c(c3)OCO4)c3cc(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-methylenedioxy-benzylamine is reacted with 4-(4-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-methylenedioxybenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH:13](Br)[C:12]2=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25]([O:27][CH3:28])=[O:26]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH:13]([O:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=1)[C:12]2=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cc(OCc3ccccc3)ccc2OCC1Br
Reactant: COC(=O)c1cccc(O)c1
Product: COC(=O)c1cccc(OC2COc3ccc(OCc4ccccc4)cc3C2=O)c1

Procedure:
By the method of Example 72, 6-benzyloxy-3-bromo-4-chromanone (49.9 g, 0.15 mol) and methyl 3-hydroxy-benzoate (22.8 g, 0.15 mol) were converted to present title product purified by chromatography on silica gel using CH2Cl2 as eluant, 2.19 g; tlc Rf 0.22 (CH2Cl2).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.C[N:9](C1C=CC=CC=1)[S:10]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]2[CH:33]=[CH:32][C:21]3=[N:22][CH:23]=[C:24]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)[CH:25]=[C:20]3[C:19](=[O:34])[C:18]=2[CH:35]=1)(=[O:12])=[O:11].N1C=CC=C(N)C=1>CS(C)=O.O>[CH3:31][N:29]1[CH:30]=[C:26]([C:24]2[CH:25]=[C:20]3[C:19](=[O:34])[C:18]4[CH:35]=[C:14]([CH2:13][S:10]([NH:9][C:3]5[CH:1]=[N:2][CH:6]=[CH:5][CH:4]=5)(=[O:12])=[O:11])[CH:15]=[CH:16][C:17]=4[CH:33]=[CH:32][C:21]3=[N:22][CH:23]=2)[CH:27]=[N:28]1
Reactant: CN1CCCC1=O
Reactant: CN(c1ccccc1)S(=O)(=O)Cc1ccc2ccc3ncc(-c4cnn(C)c4)cc3c(=O)c2c1
Agent: Nc1cccnc1
Solvent: CS(C)=O
Solvent: O
Product: Cn1cc(-c2cnc3ccc4ccc(CS(=O)(=O)Nc5cccnc5)cc4c(=O)c3c2)cn1
Temperature: 180 °C
Reaction time: 2.25 h

Procedure:
N-Methyl-2-pyrrolidinone (3 ml) was added to N-methyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-phenylmethanesulfonamide (150 mg, 0.319 mmol) and pyridin-3-amine (150 mg, 1.594 mmol) in a vial. The vial was sealed and the resulting solution was heated to 180° C. with stirring. After 2.25 h., the reaction was cooled to room temperature and diluted in DMSO and water. The resulting solution was filtered and purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA, to afford the title compound as a brown solid. 1H NMR (600 MHz, DMSO-D6) δ 9.21 (d, 1H); 8.52 (d, 1H); 8.48 (s, 1H); 8.33 (d, 1H); 8.16 (d, 1H); 8.15 (s, 1H); 8.07 (s, 1H); 7.77 (d, 1H); 7.68 (dd, 1H); 7.52 (m, 1H); 7.35 (d, 1H); 7.32 (d, 1H); 7.25 (m, 1H); 4.77 (s, 2H); 3.89 (s, 3H). LRMS (APCI) calculated for C24H19N5O3S [M+H]+, 458.1. found 458.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])/[C:16]/3=[CH:23]\[C:24]2[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=2[CH3:33])(=[O:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:34][C@@H:35]1[CH2:40][NH:39][CH2:38][C@H:37]([CH3:41])[NH:36]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>>[Cl:8][C:6]1[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])/[C:16]/3=[CH:23]\[C:24]2[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:39]3[CH2:38][C@H:37]([CH3:41])[NH:36][C@H:35]([CH3:34])[CH2:40]3)=[O:32])[C:25]=2[CH3:33])(=[O:12])=[O:11])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)cc(Cl)c4)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)cc(Cl)c4)cc32)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1

Procedure:
5-[5-(3,5-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.24 mmol) was coupled with (2R,6S)-2,6-dimethyl-piperazine (34 mg, 1.2 eq.) using HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (1.2 eq.) to give the titled compound.
Reaction SMILES: [NH2:1][C@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([Cl:18])[CH:10]=2)=[N:5]1.[CH3:20][C:21]1[NH:22][CH:23]=[C:24]([C:26](O)=[O:27])[N:25]=1>>[Cl:18][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@H:2]([NH:1][C:26]([C:24]3[N:25]=[C:21]([CH3:20])[NH:22][CH:23]=3)=[O:27])[CH3:19])[N:5]=2)[CH:16]=[C:15]([F:17])[C:12]=1[C:13]#[N:14]
Reactant: C[C@@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: Cc1nc(C(=O)O)c[nH]1
Product: Cc1nc(C(=O)N[C@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)c[nH]1
Yield: 10.4 %

Procedure:
(R)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide was prepared using the method of Example 34(d) starting from (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.0 g, 3.59 mmol) and 2-methyl-1H-imidazole-4-carboxylic acid (0.50 g, 3.95 mmol). The product purified twice by Flash-chromatography (normal phase and reverse phase). Yield 10.4%. 1H-NMR (400 MHz; DMSO): δ 1.07 (d, 3H), 2.30 (s, 3H), 4.22-4.50 (m, 3H), 7.02 (d, 2H), 7.42 (d, 1H), 7.86 (d, 1H), 7.93 (dd, 1H), 8.00 (d, HA), 8.07 (d, 1H), 12.11 (bs, 1H).