Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([O:12][CH3:13])[CH:4]=1.[CH2:14]([N:16](CC)[CH2:17]C)C.CNC>C1COCC1>[CH3:13][O:12][C:5]1[CH:4]=[C:3]([CH2:2][N:16]([CH3:17])[CH3:14])[CH:8]=[CH:7][C:6]=1[N+:9]([O-:11])=[O:10]
Reactant: CCN(CC)CC
Reactant: COc1cc(CBr)ccc1[N+](=O)[O-]
Agent: CNC
Solvent: C1CCOC1
Product: COc1cc(CN(C)C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a stirred solution of 4-(bromomethyl)-2-methoxy-1-nitrobenzene (Preparation 104, 0.2 g, 0.813 mmol) in dry THF (5 ml), was added triethylamine (0.1 g, 1 mmol) followed by a solution of dimethylamine in THF (0.5 ml of a 2M solution, 1 mmol). After stirring for 1 hour at room temperature, the solvent was removed in vacuum and the crude product was purified by silica gel column chromatography eluting with 10% methanol in ethyl acetate to afford the title compound as a white powder (0.16 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of CH2Cl6 (60 mL) and 3,5-dichlorophenol (5.0 g 30 mmol) was added tert-butyldimethylsilyl chloride (5.54 g, 36 mmol), N,N-diisoprpylethylamine (8.0 mL, 46 mmol) and a catalytic amount of 4-dimethylaminopyridine. The initially exothermic solution was stirred at ambient temperature for 6 h then diluted with CH2Cl2 (40 mL). The mixture was washed consecutively with 10% aqueous HCl (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL). the organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide 13 as a pale yellow liquied (8.8 g, 100%). 1H NMR (300 MHz, CDCl3) d 6.98 s, 1H), 6.72 (s, 2H), 0.98 (s, 9H), 0.22 (s, 6H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][N:14]([CH3:23])[C:15]1[C:20]([CH:21]=O)=[CH:19][CH:18]=[CH:17][N:16]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][N:14]([CH3:23])[C:15]1[C:20]([CH:21]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: O=C(O)CNC(=O)c1cccs1
Reactant: CN(C)c1ncccc1C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ncccc1C=C1N=C(c2cccs2)OC1=O
Temperature: 90 °C
Yield: 32.3 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 2-(dimethylamino)-3-pyridinecarboxaldehyde (50 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 29 mg of the above-captioned compound.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](=[C:11]([CH3:13])[CH3:12])[NH:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH3:17]I>CN(C)C=O>[CH3:17][N:7]1[C:8](=[C:11]([CH3:13])[CH3:12])[C:9](=[O:10])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1=[O:14]
Reactant: CCCCN1C(=O)NC(=C(C)C)C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C(=C(C)C)N(C)C1=O
Temperature: 50 °C

Procedure:
3-n-Butyl-5-(1-methylethylidene)-2,4-imidazolidinedione (3.8 g 0.02 mole) was added to a suspension of sodium hydride (0.95 g 50% oil dispersion 0.2 mole) in dry dimethylformamide (30 ml) and heated at 50° C. for five minutes. The mixture was cooled to room-temperature, methyl iodide (3.4 g 0.024 mole) added and the mixture heated at 50° C. for fifteen minutes. The mixture was then evaporated to dryness on a rotary evaporator under reduced pressure and the residue dissolved in water (100 ml) and extracted into ether (3×50 ml). The ethereal solution was dried (MgSO4) the solvent removed and the residue (title compound) distilled under reduced pressure in a Kugelrohr apparatus, b.p. 100° C. at 0.01 mm. Yield=3.8 g=92%.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:13]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:13]([N:16]([C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5])[CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Reactant: CCCNCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN(CCC)c1ccc([N+](=O)[O-])cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
2-Fluoro-5-nitrobenzaldehyde (48 mg, 0.28 mmol) was dissolved in N,N-dimethylformamide (2.4 mL), and di-n-propylamine (0.15 mL, 1.1 mmol) and potassium carbonate (0.16 g, 1.1 mmol) were added thereto, followed by stirring at 25° C. for 1 hour. After the conventional post-reaction treatment, the residue was purified by silica gel chromatography(eluted with chloroform), to obtain 2-(N,N-di-n-propylamino)-5-nitrobenzaldehyde (49 mg, 69%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](O)[CH:6]=[CH:5]2.S([O-])([O-])=O.[NH4+:17].[NH4+]>N>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([NH2:17])[CH:6]=[CH:5]2
Reactant: [NH4+]
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: N
Agent: O=S([O-])[O-]
Product: Nc1ccc2cc(Br)ccc2c1
Temperature: 190 °C
Yield: 33.5 %

Procedure:
6-Bromo-2-naphthol (2.0 g, 9 mmol), ammonium sulfite (10.4 g, 90 mmol) and 10 mL of ammonia solution were sealed in a tube. The reaction mixture was heated at 190° C. for 24 hrs and allowed to cool to room temperature, the reaction mixture was extracted with EtOAc. HCl (10%) was added to the organic layer to give a precipitate. After filtration, the solid was dissolved in 10% of Na2CO3 and extracted with EtOAc, the organic layer was dried over Na2SO4. The solvent was removed under reduced pressure to give the product as yellow solid (0.67 g, 33%). MS [M++43]=265, LC-MS: tR=2.14 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.O>CC(O)=O.[Fe]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:12]=[CH:13][CH:14]=[C:15]([NH2:16])[CH:10]2[NH2:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1cc(F)cc(F)c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: NC1=CC=CN(c2cc(F)cc(F)c2)C1N
Temperature: 100 °C

Procedure:
To a solution of N-(3,5-difluorophenyl)-3-nitro-pyridin-2-amine (2.0 g, 7.96 mmol) in AcOH (24 mL) was added iron powder (1.33 g, 23.8 mmol) and the reaction mixture was heated to 100° C. for 1 h. The reaction mixture was cooled to rt and water (70 mL) was added. The organic layer was extracted with EtOAc (350 mL) and was basified by using satd. sodium bicarbonate solution (150 mL), dried over sodium sulfate and concentrated in vacuo to provide N1-(3,5-Difluorophenyl)-pyridine-2,3-diamine. The crude product was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C(=O)([O-])[O-].[K+].[K+].[K+].[Br-]>CN(C=O)C>[N:14]1([C:2]2[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: COC(=O)c1cc(Br)ccc1OC
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-n2ccnc2)ccc1OC
Reaction time: 18 h

Procedure:
5-Bromo-2-methoxybenzoic acid, methyl ester (5 g, 20.4 mmol), imidazole (1.4 g, 20.6 mmol), and potassium carbonate (2.9 g, 20.7 mmol) were heated to 145° C. in DMF under N2 as cuprous iodide (1.5 g, 7.9 mmol) was added in portions. The reaction was stirred at this temperature for 18 h, allowed to cool, and filtered through a celite plug. The filtered salts were washed extensively with methanol, the filtrate concentrated in vacuo, and the residue taken up in ethyl acetate, washed with water, brine, and dried. Chromatography on SiO2, elution with methanol/ethyl acetate/hexanes (1:1:3) gave 3 g (63%); IR(KBr, ν=cm-1) 3430, 1726, 1512, 1232, 1068; 1H NMR (300 MHz, DMSO-d6) δ3.80 (3H, s), 3.85 (3H, s), 7.07 (1H, s), 7.27 (1H, d, J=8.8 Hz), 7.69 (1H, s), 7.76-7.82 (2H, m) 8.18 (1H, s); MS(DCl)m/z: 233 (MH+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:9][C@H:5]2[O:6][CH2:7][CH2:8][C@@:4]2([C:10]([N:12]2[CH2:21][CH2:20][C:19]3[N:18]=[CH:17][C:16]([C:22]([F:25])([F:24])[F:23])=[CH:15][C:14]=3[CH2:13]2)=[O:11])[CH2:3]1.[O:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1>>[O:26]1[CH2:31][CH2:30][CH:29]([NH:1][C@@H:2]2[CH2:9][C@H:5]3[O:6][CH2:7][CH2:8][C@@:4]3([C:10]([N:12]3[CH2:21][CH2:20][C:19]4[N:18]=[CH:17][C:16]([C:22]([F:25])([F:24])[F:23])=[CH:15][C:14]=4[CH2:13]3)=[O:11])[CH2:3]2)[CH2:28][CH2:27]1
Reactant: N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reactant: O=C1CCOCC1
Product: O=C(N1CCc2ncc(C(F)(F)F)cc2C1)[C@@]12CCO[C@@H]1C[C@@H](NC1CCOCC1)C2

Procedure:
The title compound was prepared from reaction of the product of Example 1, Step G and tetrahydro-4H-pyran-4-one following the procedure described in Example 1, Step H. 1H NMR (CHLOROFORM-d) δ: 8.72 (br. s., 1H), 7.70 (br. s., 1H), 5.04 (d, J=4.6 Hz, 1H), 4.78 (br. s., 2H), 3.95 (s, 2H), 3.97 (s, 3H), 3.53-3.75 (m, 2H), 3.28-3.49 (m, 2H), 3.14 (br. s., 2H), 2.62-2.81 (m, 1H), 2.29 (dd, J=12.8, 5.5 Hz, 3H), 1.99-2.17 (m, 1H), 1.60-1.92 (m, 3H), 1.18-1.57 (m, 5H). Calculated for C22H28F3N3O3: 440.2 (M+1). found: 440.2.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[C:15]3[CH2:23][N:22]([C:24]4[CH:25]=[N:26][C:27]([O:34][CH3:35])=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=O)(C)(C)C.[ClH:36].C(OCC)C>C(Cl)Cl>[ClH:36].[ClH:36].[CH3:35][O:34][C:27]1[N:26]=[CH:25][C:24]([N:22]2[CH2:21][CH2:20][C:16]3[N:17]=[CH:18][N:19]=[C:14]([O:13][C@H:10]4[CH2:11][CH2:12][NH:8][CH2:9]4)[C:15]=3[CH2:23]2)=[CH:29][C:28]=1[C:30]([F:33])([F:31])[F:32]
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)OC(C)(C)C)C4)c3C2)cc1C(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 128 %

Procedure:
(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 1.69 mmol) in CH2Cl2 (5 mL) was added 2M anhydrous HCl in diethyl ether (25.3 mL, 50.5 mmol) and the mixture stirred at rt for 3 h. The resulting precipitate was filtered and washed with diethyl ether to give 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine dihydrochloride as a yellow solid (1.01 g, 128% yield). [M+H]+=396.0, Rt(4)=0.71 min. The free base can be generated by partitioning the dihydrochloride salt between dichloromethane and 1N sodium hydroxide solution(aq), separating the organic phase and evaporating in vacuo. [M+H]+=396.0, Rt(4)=0.71 min.
Reaction SMILES: [C:1]1([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1.[BH4-].[Na+]>CO.O>[CH:1]1([C:11]2[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: N#Cc1ccc(C2=NCCc3ccccc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(C2NCCc3ccccc32)cc1
Yield: 89.7 %

Procedure:
A solution of 3.48 g of 4-(3,4-dihydro-isoquinolin-1-yl)-benzonitrile in 90 ml of methanol was cooled to 5° C. while stirring and treated with 1.7 g of sodium borohydride within 30 min. After completion of the addition, the mixture was stirred at 5° C. for a further 30 min. Subsequently, 50 ml of water were slowly added dropwise and the mixture was stirred at room temperature for a further 10 min. The mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated. 3.15 g of crystalline (RS)-4-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-benzonitrile were obtained. Recrystallization of a sample from diisopropyl ether gave colorless crystals of m.p. 94°-97° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]3[C:19](OS(C(F)(F)F)(=O)=O)=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C([Sn](CCCC)(CCCC)[C:37]1[S:38][CH:39]=[CH:40][N:41]=1)CCC>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][CH2:17][C:18]3[C:19]([C:37]4[S:38][CH:39]=[CH:40][N:41]=4)=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: COc1ncccc1CN1CCC(CCc2cccnc2OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ncccc1CN1CCC(CCc2cccnc2-c2nccs2)CC1
Yield: 30.3 %

Procedure:
150 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-[2-[((trifluoromethyl)sulfonyl]oxy]-3-pyridyl]ethyl]piperidine, 180 mg of 2-(tributylstannyl)thiazole and 20 mg of tetrakis(triphenylphosphine)palladium were suspended in 4 ml of toluene, and the mixture was heated under reflux for 2 hours under nitrogen flow. The solvent was evaporated, and the residue was purified by NH form silica gel column chromatography (ethyl acetate:hexane=1:4), to give 39 mg of the title compound as a colorless oil.
Reaction SMILES: [BH4-].[Li+].[CH2:3]([O:19][CH2:20][CH:21]([CH2:27][S:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:22](OCC)=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O>O1CCCC1>[CH2:3]([O:19][CH2:20][CH:21]([CH2:27][S:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:22][OH:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCOCC(CSCCCCCCCCCCCCCCCC)C(=O)OCC
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOCC(CO)CSCCCCCCCCCCCCCCCC
Yield: 68.1 %

Procedure:
To a slurry of 1.04 g of lithium borohydride in tetrahydrofuran at ambient temperature is added 29 g of ethyl 3-(hexadecyloxy)-2-[(hexadecylthio)methyl]propanoate followed by heating at reflux for 18 hours. The mixture is poured into water containing a small amount of acid followed by extraction with ether to give after drying and evaporation, a residue which is columned on silica gel using 30:1 hexane:ethyl acetate. Fractions containing the product are evaporated to give 18.4 g of the desired product.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[C:5]([C:11]#[N:12])=[C:4]([OH:13])[C:3]=1[CH3:14].[CH3:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=1>CC(O)C.C(OCC)(=O)C>[CH2:16]([O:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[C:5]([C:11]#[N:12])=[C:4]([OH:13])[C:3]=2[CH3:14])=[CH:22][CH:23]=1)[CH3:15]
Reactant: CCOc1ccc(N)cc1
Reactant: Cc1c(O)c(C#N)c2ccnn2c1Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCOc1ccc(Nc2c(C)c(O)c(C#N)c3ccnn23)cc1
Temperature: 25 °C
Yield: 56 %

Procedure:
The crude product (9.25 mg) of 7-chloro-5-hydroxy-6-methylpyrazolo[1,5-a]pyridine-4-carbonitrile (13) was dissolved in 2-propanol (2.2 mL). To this solution, p-phenetidine (289 μL) was added and the mixture was stirred under reflux with heating for 3 days. After cooled to room temperature, the reaction solution was diluted with ethyl acetate. This solution was washed with a mixture of brine and 1 mol/L hydrochloric acid (1:1) and then with a mixture of brine and saturated aqueous sodium hydrogen carbonate solution (9:1) and dried over sodium sulfate. After the solvent was removed under reduced pressure, the residue was purified with silica-gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (21) (77.8 mg, Yield 56%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([Cl:18])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(C(=O)O)c(C(F)(F)F)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Cl)c(C(F)(F)F)n1
Reaction time: 1.5 h

Procedure:
A solution of 0.45 g of 6-methyl-2-trifluoromethylpyridin-3-ylcarboxyi ic acid in 20 ml of dichloromethane is charged initially, 3 drops of dimethylformamid c are added and the mixture is subsequently treated with 1.6 ml of oxalyl chloride. After the intensive evolution of gas has ceased, the mixture is kept at a bath temperature of 40° C. for another 1.5 hours and then evaporated. The crude product (0.56 g) that remains as residue can be directly reacted further. 1H NMR (CDCl3, ppm): 8.20 (1H,d); 7.51 (1H,d); 2.65 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7](Br)[CH:6]=1)[CH3:2].[CH:14]([Zn]C(C)C)([CH3:16])[CH3:15]>O1CCOCC1.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]>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([CH:14]([CH3:16])[CH3:15])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Cl)c(Br)c1
Reactant: CC(C)[Zn]C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(Cl)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Bromo-4-chlorobenzoic acid ethyl ester (1.05 g, 3.99 mmol) was added in one portion to a solution of diisopropylzinc (10.0 mmol, 1M toluene, Aldrich) in 10 mL of 1,4-dioxane followed by addition of Pd(dppf)2Cl2 (4.0 mmol). The mixture was heated to reflux 3 hours, cooled to ambient temperature and stirred overnight. The mixture was quenched with 1N aqueous HCl, diluted with ethyl acetate, and filtered through celite. The separated organic layer was washed sequentially with 1N aqueous HCl, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by chromatography eluting with 4% ethyl acetate/hexanes to provide the title compound. 1H NMR (DMSO-d6) δ 7.92 (d, 1H), 7.78 (dd, 1H), 7.58 (d, 1H), 4.32 (q, 2H), 3.35 (sept, 1H), 1.32 (t, 3H), 1.24 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([OH:15])=O)[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:44][C:45]1[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:44][C:45]3[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=3)=[O:15])[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: Nc1ccncc1
Reactant: O=C(O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CN1C[C@@H]2COCCN2c2nc(Cl)ncc21)Nc1ccncc1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x26 using (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetic acid (PREPARATION x25, 50 mg, 0.176 mmol), HATU (87 mg, 0.228 mmol), 4-aminopyridine (25 mg, 0.263 mmol) and triethylamine (0.073 mL, 0.527 mmol) in DMF (2 mL). ESI-MS m/z [M+H]+ calc'd for C16H17ClN6O2, 361.12; found 361.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11](O)(=O)[CH:12]([CH3:14])[OH:13].Cl.[OH-].[NH4+]>>[OH:13][CH:12]([C:14]1[NH:1][C:2]2[C:3]([O:9][CH3:10])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=1)[CH3:11]
Reactant: COc1cccc(N)c1N
Reactant: CC(O)C(=O)O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: COc1cccc2nc(C(C)O)[nH]c12
Temperature: 100 °C

Procedure:
2,3-Diaminoanisole (5.88 g) and lactic acid (5.6 ml) were combined, treated with concentrated hydrochloric acid (45 ml) and heated at 100° C. for 18 h. The reaction was cooled to 0° C., neutralised with ammonium hydroxide solution and extracted with ethyl acetate (3×45 ml). The combined organic layers were dried over magnesium sulphate, filtered and the filtrate evaporated in vacuo and the residue purified by flash chromatography on silica eluting with ethyl acetate to yield the desired product as a reddish-brown solid (4.91 g).
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:16].[C:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][C:21]=1[O:30][CH2:31][CH3:32])#[N:19]>C1COCC1.C1COCC1.CN(C=O)C>[C:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:4])=[O:17])=[C:8]2[CH3:16])(=[O:28])=[O:27])=[CH:22][C:21]=1[O:30][CH2:31][CH3:32])#[N:19]
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C#N
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOc1cc(S(=O)(=O)n2c(C)c(CC(=O)O)c3cccnc32)ccc1C#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred, ice-cooled (0° C.) suspension of sodium hydride (26.3 mg of a 60% dispersion in mineral oil, 0.686 mmol) in dry THF (10 ml) under an inert atmosphere of Argon is added dropwise (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((0.1 g, 0.49 mmol) in THF/DMF (4 ml of a 3:1 mixture). The reaction mixture is stirred at 0° C. for 1 hour and then treated with 4-cyano-3-ethoxy-benzenesulfonyl chloride (168 mg, 0.686 mmol) in dry THF (1 ml). Stirring continued at 0° C. for 10 minutes and at room temperature for 10 minutes and then the reaction mixture is poured onto water (50 ml). The mixture is extracted with ethyl acetate (2×50 ml) and the organic portions are combined, washed brine (50 ml), dried (MgSO4) and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with iso-hexane/ethyl acetate (0%-20% ethyl acetate) to yield the titled product. (MH+ 414).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)[CH3:2].[S:13]([O-:17])([O-:16])(=[O:15])=[S:14]>>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([N:3]([CH2:1][CH3:2])[CH2:11][CH3:12])=[CH:5][C:6]=1[S:14][S:13](=[O:16])(=[O:15])[OH:17]
Reactant: O=S([O-])([O-])=S
Reactant: CCN(CC)c1ccc(N)cc1
Product: CCN(CC)c1ccc(N)c(SS(=O)(=O)O)c1

Procedure:
In this step, an N,N-diethyl-1,4-diamino-benzene, 15, is oxidized in the presence of a thiosulfate to give a thiosulfuric acid S-(2-amino-5-diethylamino-phenyl) ester, 16, as illustrated in the following scheme: