Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH2:25])[CH:19]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:25][CH2:24][C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)[N:3]=1
Reactant: NCc1cccnc1
Reactant: CS(=O)(=O)c1nc(Cl)c(C#N)c(NCCO)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(Cl)nc(NCc2cccnc2)nc1NCCO

Procedure:
In analogy to the procedure described in example 47a, the crude 4-chloro-6-(2-hydroxy-ethylamino)-2-methanesulfonyl-pyrimidine-5-carbonitrile was treated with 3-picolyl-amine in dioxane in the presence of N-ethyl-diisopropylamine at 40° C. to yield 4-chloro-6-(2-hydroxy-ethylamino)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile as a brown solid which was used in the next step without further purification and characterization.
Reaction SMILES: [CH2:1]([N:8]1[C:17](Cl)=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([S:22]CC)[CH3:21].[Na]>>[CH2:1]([N:8]1[C:17]([S:22][CH2:20][CH3:21])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2ccccc2cc(Cl)n1Cc1ccccc1
Reactant: CCSCC
Agent: [Na]
Product: CCSc1cc2ccccc2c(=O)n1Cc1ccccc1

Procedure:
By following the same procedure as in Example 1 using 0.5 g. of 2-benzyl-3-chloro-1-oxo-1,2-dihydroisoquinoline and 0.6 g. of an aqueous solution of 20% sodium ethylsulfide, 0.37 g. of 2-benzyl-3-ethylthio-1-oxo-1,2-dihydroisoquinoline was obtained (recrystallized from cyclohexane).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:20](OCC)(OCC)(OCC)[CH3:21]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH3:20][C:21]1[N:12]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CCOC(=O)CCNc1c(N)cnc2ccccc12
Reactant: CCOC(C)(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCOC(=O)CCn1c(C)nc2cnc3ccccc3c21
Yield: 61.5 %

Procedure:
Ethyl N-(3-aminoquinolin-4-yl)-β-alaninate (9.0 g, 35 mmol) was treated with triethyl orthoacetate (8.91 mL, 48.6 mmol) and pyridinium p-toluenesulfonate (0.200 g) according to the method described in Part A of Example 10 to provide 6.10 g of ethyl 3-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate. The reaction was complete in two hours, and a precipitate was removed by filtration from the organic layer during the work-up procedure.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(O)=[O:2].[NH2:16]C(N)=O>O>[CH3:15][O:14][C:12]1[CH:13]=[C:5]2[C:6](=[CH:10][CH:11]=1)[C:7](=[O:8])[NH:16][C:1](=[O:2])[CH2:4]2
Reactant: COc1ccc(C(=O)O)c(CC(=O)O)c1
Reactant: NC(N)=O
Solvent: O
Product: COc1ccc2c(c1)CC(=O)NC2=O
Temperature: 25 °C

Procedure:
2-Carboxymethyl-4-methoxy-benzoic acid (946 mg, 4.5 mmole) and urea (629 mg, 10.4 mmole) is stirred and heated using an oil bath at 180° C. After one hour the mixture is cooled to room temperature and treated with water, collected by filtration, washed with water and dried to give a brown solid, 498 mg, (57%); mp 212-5° C., MS (ESI): m/z 192.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:20][C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: Oc1ccc(F)cc1
Reactant: COC(=O)c1cc(Br)cnc1Cl
Product: COC(=O)c1cc(Br)cnc1Oc1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 56 from methyl 5-bromo-2-chloronicotinate (J. Org. Chem. 1989, 54, 3618–3624) and 4-fluorophenol: 1H-NMR (CDCl3) δ 8.37 (1H, d, J=2.5 Hz), 8.27 (1H, d, J=2.5 Hz), 7.10 (2H, d, J=6.2 Hz), 3.95 (3H, s); MS (ESI) m/z 326 (M+H)+.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][Si](C)(C)C)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1COCC1.C([O-])([O-])=O.[K+].[K+]>CO>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:9][CH:10]=1)#[CH:15]
Reactant: CCCCCCOc1ccc(C#C[Si](C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc(OCCCCCC)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 500 mL round bottom flask was added ((4-(hexyloxy)phenyl)ethynyl)trimethylsilane, 6, (14.95 g, 54.7 mmol, 1.0 equiv.) followed by THF (100 mL, 0.5 M), MeOH (100 mL, 0.5 M) and saturated aqueous K2CO3 (100 mL, 0.5 M). The mixture was stirred rapidly at room temperature for 4 hours. After 4 hours, the mixture was diluted with hexanes and rinsed with H2O (3×). The organic layer was dried with MgSO4 and the organics were filtered through a thin SiO2 pad with 5% ethyl acetate/95% hexanes to give 1-ethynyl-4-(hexyloxy)benzene, 3, as a clear oil (10.9 g, 54.2 mmol, 99%). 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 3.99 (t, J=6.4 Hz, 2H), 3.02 (s, 1H), 1.81 (ap. p, J=8.0 Hz, 2H), 1.53-1.40 (m, 2H), 1.40-1.32 (m, 4H), 0.94 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:15]=[C:14](S(C)(=O)=O)[N:13]=2)=[CH:4][CH:3]=1.[CH2:25]([NH2:27])[CH3:26]>C(O)C>[CH2:25]([NH:27][C:14]1[N:13]=[C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=2)[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:15]=1)[CH3:26]
Reactant: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(S(C)(=O)=O)n1
Reactant: CCN
Solvent: CCO
Product: CCNc1nc(-c2ccc(F)c3ccccc23)cc(C(C)C)n1
Reaction time: 6 h
Yield: 49 %

Procedure:
4-(4-fluoronaphth-1-yl)-6-isopropyl-2-methanesulfonylpyrimidine (0.100 g, 0.29 mmol) was added to a solution of ethylamine (0.33 mL, 5.8 mmol) in ethanol (1 mL). The reaction vessel was placed in a sonication bath for 6 hours at a bath temperature of 45° C. The ethanol was removed in vacuo leaving a viscous oil. The oil was crystallized from ethanol and water to give 2-ethylamino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine (49%), m.p. 77-78° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17].[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
Triethylamine (2.65 g, 26.2 mmol) was slowly added to a mixture of 2-mercapto-benzoic acid methyl ester (4.0 g, 23.8 mmol) and trityl chloride (6.63 g, 23.8 mmol) in CH2Cl2 at rt. The reaction mixture was stirred at rt for 3 h and washed with water (100 mL). The two phases were separated and the aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to provide 2-tritylsulfanyl-benzoic acid methyl ester (9.6 g), which was used directly to the next reaction without further purification. MS ESI(+) m/e: 411.15 (M+1).
Reaction SMILES: [C:1]([C:5]1([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([C:23]3[O:24][C:25]4[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][C:26]=4[CH:27]=3)([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][C:13]=2[CH3:35])[O:9][CH2:8][CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.Cl.C[O:42][C:43](=[O:46])[CH2:44][NH2:45]>CN(C1C=CN=CC=1)C>[C:1]([C:5]1([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([C:23]3[O:24][C:25]4[CH:31]=[CH:30][C:29]([C:32]([NH:45][CH2:44][C:43]([OH:46])=[O:42])=[O:33])=[CH:28][C:26]=4[CH:27]=3)([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:14][C:13]=2[CH3:35])[O:9][CH2:8][CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(CC)(c1ccc(OCC2(C(C)(C)C)OCCO2)c(C)c1)c1cc2cc(C(=O)O)ccc2o1
Reactant: COC(=O)CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC2(C(C)(C)C)OCCO2)c(C)c1)c1cc2cc(C(=O)NCC(=O)O)ccc2o1
Yield: 89.4 %

Procedure:
2-{1-[4-(2-tert-butyl-[1,3]dioxolan-2-ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-5-carboxylic acid (125 mg, 0.260 mmol), EDC (75 mg, 0.391 mmol), DMAP (95 mg, 0.781 mmol), and glycine methyl ester hydrochloride (49 mg, 0.39 mmol) are reacted to produce the intermediate followed by hydrolysis analogous to Example 1, step K to give title compound (125 mg, 90%).
Reaction SMILES: [NH2:1][Al]CCl.[F:5][C:6]([F:24])([C:20]([F:23])([F:22])[F:21])[CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:18]#[N:19])[N:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=12.CO>C1(C)C=CC=CC=1>[F:24][C:6]([F:5])([C:20]([F:21])([F:23])[F:22])[CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:18](=[NH:1])[NH2:19])[N:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=12
Reactant: N#Cc1nc(CCC(F)(F)C(F)(F)F)c2ncccn12
Reactant: N[Al]CCl
Solvent: Cc1ccccc1
Solvent: CO
Product: N=C(N)c1nc(CCC(F)(F)C(F)(F)F)c2ncccn12
Temperature: 107 °C
Reaction time: 0.5 h

Procedure:
A solution of amino(chloro)methylaluminum (0.5 M in toluene, 18.13 mL, 9.06 mmol) was added quickly to a stirred solution of the intermediate from Step F (0.3006 g, 1.036 mmol) in toluene (12.63 mL) and the mixture was heated at 107° C. overnight. The reaction mixture was cooled to room temperature, MeOH was added and the mixture was stirred for 30 min. The reaction mixture was filtered through a plug of Celite™ (diatomaceous earth), washed through with 2M NH3 in MeOH and the filtrate was concentrated in vacuo to give the crude product. This was purified by flash chromatography using a DCM/MeOH (2 N NH3 in MeOH) gradient to afford the desired product, as a yellow solid. m/z=308.0 (M+H).
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH:8]3[CH2:10][C:4]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:21][CH2:20][NH:19][C:18]5=[O:22])=[CH:13][CH:12]=4)([CH2:5][CH:6]1[CH2:7]3)[CH2:3]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[C:38]#[N:39])=[O:32]>CS(C)=O.CCOC(C)=O>[O:22]=[C:18]1[NH:19][CH2:20][CH2:21][N:17]1[C:14]1[CH:13]=[CH:12][C:11]([C:4]23[CH2:10][CH:8]4[CH2:9][C:2]([NH:1][CH2:30][C:31]([N:33]5[CH2:37][CH2:36][CH2:35][C@H:34]5[C:38]#[N:39])=[O:32])([CH2:3]2)[CH:6]([CH2:7]4)[CH2:5]3)=[CH:16][CH:15]=1
Reactant: NC12CC3CC1CC(c1ccc(N4CCNC4=O)cc1)(C3)C2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(c1ccc(N4CCNC4=O)cc1)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.9 %

Procedure:
To a stirred mixture of the compound obtained from step II (0.4 g, 1.35 mmol) and K2CO3 (0.56 g, 4.05 mmol) in DMSO (6 mL) at ice bath temperature under N2 atmosphere was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.23 g, 1.35 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-[4-(2-oxoimidazolidin-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as an off-white solid (0.21 g) in 36% yield. m/z (M+1) 434; 1H NMR (CDCl3) 300 MHz δ 7.45 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.8 Hz, 2H), 4.86-4.76 (m, 1H), 4.67 (s (br), 1H), 3.93 (t, J=7.4 Hz, 2H), 3.75-3.40 (m, 4H), 3.48 (s, 2H), 3.46-2.38 (m, 1H), 2.36-2.23 (m, 2H), 2.23-1.70 (m, 12H), 1.65-1.57 (m, 1H).
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]=[C:16]1[CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CO[Na].[CH3:33][O:34][CH:35]([O:39][CH3:40])N(C)C>CO>[CH3:33][O:34][CH:35]([O:39][CH3:40])[N:27]1[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22][C:16]2[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:15]=2)[CH2:29][CH2:28]1
Reactant: C1CCNC(CCC2CCNCC2)=NC1
Reactant: COC(OC)N(C)C
Agent: CO[Na]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Product: COC(OC)N1CCC(CCC2=NCCCCN2)CC1
Temperature: 90 °C

Procedure:
The dihydrochloride salt of 4-[2-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl)ethyl]piperidine (1.6 g, 5.8 mM) in methanol (12 ml) which contained MeONa (12 mM) and dimethylformamide dimethyl acetal (20 ml) was heated at 90° C. for 8 hrs. The excess of dimethylformamide dimethylacetal was removed in vacuo to give the 4-[2-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl)ethyl] 1-piperidinecarboxaldehyde dimethylacetal. To the mixture of 6-aminopenicillanic acid (1.1 g, 5 mM) and diisopropylethylamine (0.96 ml) in 20 ml dry CHCl3 was added the solution (CHCl3 8 ml: MeOH 1 ml) of the above piperidine-carboxaldehyde dimethylacetal at 0° C. The reaction was stirred at 0° C. for 1 hr and then at room temperature for 3 hrs. The solvent was then removed, and water added (30 ml). The aqueous solution, washed with ethylacetate, was acidified to pH 3 with dilute aqueous HCl and purified on Sephadex LH 20 column to yield [2S-(2alpha,5alpha,6beta)]-6-[[[4-[2-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl)ethyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrochloride (0.85 g, 38% yield)
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[NH:20][C:19](=O)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:6]=1)(=[O:3])[CH3:2].S(Cl)([Cl:24])=O>CN(C=O)C>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:20]=[C:19]([Cl:24])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(-c2nc3ccccc3c(=O)[nH]2)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc(-c2nc(Cl)c3ccccc3n2)c1
Temperature: 25 °C

Procedure:
To 3-(4-oxo-3,4-dihydroquinazolin-2-yl)phenyl acetate was added thionyl chloride (100 mL) and DMF (2 mL) and the reaction was heated to reflux for 4 h. The flask was allowed to cool to RT and then concentrated in vacuo. The crude product was azeotroped with toluene (2×50 mL), taken up in CH2Cl2 (300 mL) and washed with saturated NaHCO3 (3×50 mL), water (1×50 mL) and brine (1×50 mL), dried with MgSO4 and concentrated in vacuo to give 3-(4-chloroquinazolin-2-yl)phenyl acetate. (9.77 g, mmol, 100%).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[C:19]([CH3:24])[C:20](=[O:23])[CH2:21][CH3:22])=[CH:14][CH:13]=1.[C:25]([O:32][CH2:33][CH3:34])(=[O:31])[C:26]([O:28]CC)=O>C1COCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]=[C:19]([CH3:24])[C:20](=[O:23])[CH:21]([CH3:22])[C:26](=[O:28])[C:25]([O:32][CH2:33][CH3:34])=[O:31])=[CH:16][CH:17]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC(=O)C(C)=Cc1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(C)C(=O)C(C)=Cc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of LiHMDS (1N solution in THF, 5.48 mmol, 5.17 mL) in THF (16 mL) at −78° C. was added a solution of 46b (4.98 mmol, 1.04 g) in THF (2.5 mL) drop wise. After stirring at −78° C. for 1 h, the mixture was treated with a solution of diethyl oxalate (4.98 mmol, 0.73 g) in THF (2.5 mL). After stirring at −78° C. for 1 h, then the mixture was warmed up to room temperature and stirred overnight. The solvent was evaporated and the crude product was taken up in EtOAc, and washed with 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated to give 1.5 g of 46c.
Reaction SMILES: [CH2:1](Br)[CH3:2].[Li].[CH3:5][C:6]1([CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9][C:8]([CH3:14])([CH3:13])[C:7]1=[O:15]>C(OCC)C>[CH2:1]([C:7]1([OH:15])[C:8]([CH3:14])([CH3:13])[CH2:9][CH2:10][CH2:11][CH2:12][C:6]1([CH3:16])[CH3:5])[CH3:2]
Reactant: CC1(C)CCCCC(C)(C)C1=O
Reactant: CCBr
Agent: [Li]
Solvent: CCOCC
Product: CCC1(O)C(C)(C)CCCCC1(C)C
Temperature: -30 °C
Yield: 76.4 %

Procedure:
A mixed solution of ethyl bromide (33.30 g, 0.40 moles)/dried diethyl ether (40 ml) was dropped into a mixture of lithium (4.30 g, 0.62 moles)/dried diethyl ether (25 ml) in 2 hours while stirring at -30° C., followed by further adding dried diethyl ether (40 ml) and raising the temperature to 0° C. The mixture was subjected to separation by filtration. The resulting filtrate was dropped into a mixed solution of 2,2,7,7-tetramethylcycloheptanone (15.00 g, 0.09 moles)/dried diethyl ether (40 ml) in 30 minutes while stirring at 0° C. The mixture was stirred at 0° C. for 2 hours. The resulting reaction mixture was treated in the same manner as in Example 1 to obtain 13.50 g (yield 76.4%) of the captioned compound. This compound was a colorless transparent liquid having a woody, earthy and patchuli oil-like odor.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([OH:17])[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[NH:20]1[CH:29]2[CH:24]([CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:23][CH2:22][CH2:21]1>>[OH:17][C:15]1[CH:16]=[C:8]([CH:9]=[C:10]([C:11]([N:20]2[CH:29]3[CH:24]([CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:23][CH2:22][CH2:21]2)=[O:13])[CH:14]=1)[O:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:19][CH:18]=1
Reactant: N#Cc1ccc(Oc2cc(O)cc(C(=O)O)c2)cc1
Reactant: C1CCC2NCCCC2C1
Product: N#Cc1ccc(Oc2cc(O)cc(C(=O)N3CCCC4CCCCC43)c2)cc1
Yield: 72.4 %

Procedure:
3-(4-Cyano-phenoxy)-5-hydroxy-benzoic acid (1.5 g, 5.87 mmol) and decahydro-quinoline (0.89 g, 6.45 mmol) and other reagents as described in Example 9(e) were used to afford 1.6 g of the required product. NMR (DMSO-d6): δ 1.35 (6H, m), 1.80 (7H, m), 3.0 (1H, m), 3.6 (1H, m), 4.5 (1H, m), 6.44 (1H, s), 6.54 (2H, m), 7.16 (2H, d), 7.88 (2H, d), 10.1 (1H, brs).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[BrH:18].[NH+]1C=CC=CC=1>O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[CH2:11][Br:18])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Br
Reactant: CCOC(=O)C(=NOC)C(C)(OCC)OCC
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(=NOC)C(CBr)(OCC)OCC

Procedure:
Ethyl 2-methoxyimino-3,3-diethoxybutyrate (syn isomer, 10.0 g), pyridinium hydrobromide perbromide (15.5 g) and tetrahydrofuran (100 ml) were treated in a similar manner to that of Example 8 (2) to give ethyl 2-methoxyimino-3,3-diethoxy-4-bromobutyrate (syn isomer, 16.20 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[CH:15]=1)[C:10]([OH:12])=O)[OH:6])[CH3:2].Cl.Cl.[CH3:27][C:28]1[N:33]=[CH:32][C:31]([C@H:34]([NH2:36])[CH3:35])=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[CH:15]=1)[C:10]([NH:36][C@@H:34]([C:31]1[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=1)[CH3:35])=[O:12])[OH:6])[CH3:2]
Reactant: Cc1ccc([C@@H](C)N)cn1
Reactant: CCN(CC)CC(O)c1cc(C(=O)O)cc(-c2ccc(C)cn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)CC(O)c1cc(C(=O)N[C@H](C)c2ccc(C)nc2)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(2-(diethylamino)-1-hydroxyethyl)-5-(5-methylpyridin-2-yl)benzoic acid (30 mg, 0.075 mmol) in N,N-dimethylformamide (5 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (100 mg, 0.48 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (160 mg, 0.42 mmol) and N,N-diisopropylethylamine (300 μL, 1.7 mmol). The reaction mixture was stirred for 16 hours at 25° C. and purified by preparative HPLC (100×21.2 mm C18 column, CH3CN/water[10 mM Et2NH]) to afford the title product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH:4](Br)[CH3:5].[CH:8]([S:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1)([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:7])[CH:4]([O:18][C:17]1[C:12]([S:11][CH:8]([CH3:10])[CH3:9])=[N:13][CH:14]=[CH:15][CH:16]=1)[CH3:5]
Reactant: CC(C)Sc1ncccc1O
Reactant: COC(=O)C(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cccnc1SC(C)C
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
12.3 ml of 2-bromopropionic acid methyl ester are added dropwise at room temperature to a mixture of 16.9 g of 2-isopropylthio-3-hydroxypyridine and 15.2 g of potassium carbonate in 250 ml of dimethylformamide and the batch is stirred for 75 minutes. The suspension is introduced into a mixture of ice-water (300 ml), 50 ml of 2N hydrochloric acid and 300 ml of ethyl acetate, washed four times with 120 mi of water and 120 mi of ethyl acetate each time, and the organic phase is dried over sodium sulfate and concentrated by evaporation. 25.4 g of the desired intermediate are obtained in the form of a viscous oil.
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:8]2[CH:23]=[C:24]([Cl:26])[CH:25]=[C:7]2[C:6]=1[OH:27])=[O:4].[NH2:28][CH2:29][C:30]([O-:32])=[O:31].[Na+]>>[Cl:26][C:24]1[CH:25]=[C:7]2[C:6]([OH:27])=[C:5]([C:3]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:17][CH:18]=3)[N:8]2[CH:23]=1
Reactant: NCC(=O)[O-]
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(C(F)(F)F)cc2)c1=O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(C(F)(F)F)cc2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 6-chloro-4-hydroxy-2-oxo-1-(4-trifluoromethyl-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 444 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]1([S:13]([C:16]2[C:17]([S:27][CH3:28])=[N:18][N:19]3[C:24](Cl)=[CH:23][C:22]([CH3:26])=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[C:7]1([S:13]([C:16]2[C:17]([S:27][CH3:28])=[N:18][N:19]3[C:24]([N:1]4[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]4)=[CH:23][C:22]([CH3:26])=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CNCCN1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CSc1nn2c(N3CCNCC3)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
0.3 g (3.4 mmol) of piperazine in 10 ml of DMF was added to a solution of 0.6 g (1.7 mmol) of 3-benzenesulphonyl-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 10 ml of DMF and the mixture was stirred at 60° C. for 2 hrs. The reaction solution was cooled to RT and evaporated in a high vacuum. The residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 8:1) and crystallization from EtOH yielded 0.35 g (51%) of 3-benzenesulphonyl-5-methyl-2-methylsulphanyl-7-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p. 201-202°.