Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:7]=1.[C:22]([O:26][C:27](=[O:50])[N:28]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:29]1[S:30][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:33]=1)([CH3:25])([CH3:24])[CH3:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.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>[C:22]([O:26][C:27]([N:28]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:29]1[S:30][C:31]([C:2]2[CH:3]=[C:4]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]3[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=3)[CH:7]=2)=[CH:32][N:33]=1)=[O:50])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)c1cn2cc(Br)cc(-c3ccccc3)c2n1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(B2OC(C)(C)C(C)(C)O2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn2cc(-c3cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s3)cc(-c3ccccc3)c2n1
Temperature: 80 °C
Yield: 17.1 %

Procedure:
A solution of ethyl 6-bromo-8-phenylimidazo[1,2-a]pyridine-2-carboxylate (0.10 g, 0.29 mmol) and tert-butyl(tert-butoxycarbonyl)(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate (0.14 g, 0.33 mmol) in toluene (3 mL) and ethanol (1 mL) was bubbled nitrogen for 20 mins. The mixture was then treated with Pd(PPh3)4 (30 mg, 0.026 mmol) and K3PO4 (2 M, 1 mL, 2 mmol) and heated at 80° C. overnight. The reaction was cooled, poured into ethyl acetate (200 mL), washed with brine, separated, and concentrated. The residue was purified by column chromatography using ethyl acetate in hexanes (10-30%) as eluent. The product containing fractions were concentrated to give 28 mg (15% yield) of ethyl 6-(2-(bis(tert-butoxycarbonyl)-amino)thiazol-5-yl)-8-phenylimidazo[1,2-a]pyridine-2-carboxylate as a white solid. LCMS (Conditions C): 4.15 min (RT); (M+H)+=565.62 (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:20])[CH:18]=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH:21]1[CH2:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+:27]>O>[CH:22]12[CH2:21][CH:25]([CH:24]=[CH:23]1)[CH:18]([C:17](=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[NH:27]2
Reactant: C1=CCC=C1
Reactant: [NH4+]
Reactant: COc1cc(CCCCC(=O)C=O)cc(OC)c1OC
Agent: [Cl-]
Solvent: O
Product: COc1cc(CCCCC(=O)C2NC3C=CC2C3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 0.75 g (2.7 mmol) of 6-(3,4,5-trimethoxyphenyl)-2-keto-hexanal and 0.66 ml (8.0 mmol) of cyclopentadiene in 10 ml of aqueous saturated ammonium chloride was stirred at room temperature for 20 hours. The reaction mixture was diluted with 5 ml of water and extracted with 25 ml of ethyl acetate. The aqueous solution was then adjusted to pH=10 with 1N sodium hydroxide (NaOH) and extracted with ethyl acetate. These ethyl acetate layers were combined, dried (Na2SO4) and evaporated to yield 85 mg of 1-(2-Aza-bicyclo[2.2.1]hept-5-en-3-yl)-5-(3,4,5-trimethoxy-phenyl)-pentan-1-one as a mixture of exo and endo isomers. 1H NMR: (CDCl3) δ 6.40 (s, 2 H), 6.22 (m, 1 H), 5.65 (m, 1 H), 3.8 (s, 6 H), 3,75 (s, 3 H), 3.0-4.2 (m, 2 H), 2.5 (m, 5 H), 1.6 (m, 4 H), 1.4 (m, 1 H), 1.2 (m, 1 H). Mass spectrum: m/e=346.2 (p+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:26]([CH:29]1[CH2:31][CH:30]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[C:27]=[O:28].O>CN(C=O)C>[C:32]1([CH:30]2[CH2:31][CH:29]2[NH:26][C:27]([NH:1][C:2]2[N:7]=[N:6][C:5]([N:8]3[CH2:9][CH2:10][N:11]([C:14](=[O:15])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:13]3)=[CH:4][CH:3]=2)=[O:28])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C=NC1CC1c1ccccc1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)NC1CC1c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a solution of [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone (123 mg, 0.35 mmol) in DMF (20.0 mL) was added (2-isocyanatocyclopropyl)benzene (111 mg, 0.7 mmol). The mixture was stirred at 60° C. overnight. After cooling, the mixture was poured into water (120 mL). The white solid, which precipitated, was filtered off and dried in vacuum to give the title product (162 mg) as a white solid in 90% yield. 1H NMR (300 MHz, CDCl3) δ 8.01-7.97, 7.73, 7.60, 7.55, 7.32, 7.22-7.10, 7.06, 4.00-3.95, 3.87-3.86, 3.62-3.52, 3.43-3.41, 3.25-3.22, 2.85-2.82, 2.14-2.10, 0.91-0.86. MS (ES+) m/z 511.2 (M+1).
Reaction SMILES: C(CCC1C(CCCCCCOC2C=C(C3C=CC(F)=C(F)C=3)C=C(C(=O)N(C)C)C=2)=CC=CC=1OCCCC(O)=O)(O)=O.C([O:47][C:48](=[O:100])[CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][O:65][C:66]2[CH:67]=[C:68]([C:86]3[CH:91]=[CH:90][CH:89]=[CH:88][C:87]=3[F:92])[CH:69]=[C:70]([C:72](=[O:85])[NH:73][CH2:74][C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=3[O:81][CH:82]([F:84])[F:83])[CH:71]=2)[C:54]=1[CH2:93][CH2:94][C:95]([O:97]CC)=[O:96])C.[OH-].[Na+]>C1COCC1.CCO>[C:95]([CH2:94][CH2:93][C:54]1[C:55]([CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][O:65][C:66]2[CH:67]=[C:68]([C:86]3[CH:91]=[CH:90][CH:89]=[CH:88][C:87]=3[F:92])[CH:69]=[C:70]([C:72](=[O:85])[NH:73][CH2:74][C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=3[O:81][CH:82]([F:83])[F:84])[CH:71]=2)=[CH:56][CH:57]=[CH:58][C:53]=1[O:52][CH2:51][CH2:50][CH2:49][C:48]([OH:100])=[O:47])([OH:97])=[O:96]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NCc3ccccc3OC(F)F)cc(-c3ccccc3F)c2)c1CCC(=O)OCC
Agent: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)c(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NCc3ccccc3OC(F)F)cc(-c3ccccc3F)c2)c1CCC(=O)O
Yield: 90.9 %

Procedure:
The title compound was prepared by the same method as 4-{2-(2-carboxy-ethyl)-3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid starting from 4-[3-{6-[5-(2-difluoromethoxy-benzylcarbamoyl)-2′-fluoro-bi phenyl-3-yloxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (100 mg, 0.128 mmol) and 1.0 N aqueous NaOH (5 mL) in THF (5 mL) and EtOH (5 mL) to afford 4-(2-(2-carboxy-ethyl)-3-{6-[5-(2-difluoromethoxy-benzylcarbamoyl)-2′-fluoro-bi phenyl-3-yloxy]-hexyl}-phenoxy)-butyric acid (84 mg, 91%) as a white amorphous solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:23])=[C:13]([C:19](OC)=[O:20])[C:14](=[O:18])[NH:15]2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26].C[O-].[Na+].CO.Cl>O.CCO.O>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:23])=[C:13]([C:19]([NH:25][OH:26])=[O:20])[C:14](=[O:18])[NH:15]2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CO
Product: O=C(NO)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O

Procedure:
A mixture of methyl 7-benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (21 mg, 68 μmol), hydroxylamine hydrochloride (75 mg, 1.1 mmol) and 4.63 M NaOMe/MeOH (0.1 mL, 463 μmol) in 4:1 EtOH/water (1.25 mL) was heated at reflux for 2 h. The mixture was neutralized with conc. HCl, diluted with water and the resulting solids were collected by filtration. Trituration of the filter cake with EtOAc/MeOH provided the product as a beige solid: 1H NMR (d6-DMSO) δ 11.86 (2H, br), 9.78 (1H, br), 8.50 (1H, br), 7.50-7.10 (6H, m), 4.10 (2H, br s); HRMS calcd for C16H13N3O4+H+: 312.0984. Found: 312.0987.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[OH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:13](OC(=O)C)(=O)[CH3:14].[OH-].[Na+]>O>[CH3:13][C:14]1[O:12][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: CC(=O)OC(C)=O
Reactant: Nc1cnc2ccccc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2cnc3ccccc3c2o1

Procedure:
3-Aminoquinolin-4-ol (6 g) was refluxed with acetic anhydride (8 eq.) until analysis by thin layer chromatography indicated that the reaction was complete. The reaction mixture was cooled, diluted with ice and water, made basic with 10% sodium hydroxide and then extracted with dichloromethane. The extract was washed with water and brine, dried over magnesium sulfate and then concentrated under vacuum. The residue was purified by column chromatography (silica gel eluting with methanol/ethyl acetate) to provide 5.1 g of 2-methyloxazolo[4,5-c]quinoline.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17].O>CN(C=O)C>[F:7][C:6]([F:9])([F:8])[C:5]([N:4]([CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=[CH2:12])[CH3:3])=[O:10]
Reactant: CNC(=O)C(F)(F)F
Reactant: C=CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCCCN(C)C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 56 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 31.5 g, 1.28 eq.) was slowly added under nitrogen atmosphere to a solution of N-methyl-2,2,2-trifluoroacetamide (100 g, 1.28 eq.) in DMF (500 mL) at 0° C. The reaction mixture was stirred for 90 min at 0° C., and then 6-bromo-1-hexene (100 g, 1 eq.) was added dropwise over 45 min. The reaction mixture was allowed to warm up to room temperature, and stirred for 3 days at room temperature. The reaction mixture was then poured into water and extracted tree time with EtOAc. The combined organics layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to produce compound 31a as colorless oil in 56% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 1.27-1.38 (m, 2H), 1.48-1.60 (m, 2H), 2.00-2.06 (m, 2H), 2.93-3.07 (2m, 3H), 3.35-3.40 (m, 2H), 4.92-5.04 (m, 2H), 5.73-5.83 (m, 1H).
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[F:15][C:16]([F:37])([F:36])[C:17]([OH:35])([CH3:34])[C:18]#[C:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.C(OCC)C>[F:37][C:16]([F:15])([F:36])[C:17]([OH:35])([CH3:34])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)(=[O:27])=[O:28])=[CH:22][CH:21]=1
Reactant: CC(O)(C#Cc1ccc(S(=O)(=O)N2CCCC2)cc1)C(F)(F)F
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(O)(/C=C/c1ccc(S(=O)(=O)N2CCCC2)cc1)C(F)(F)F
Yield: 88.9 %

Procedure:
To a solution of sodium bis(methoxyethoxy) aluminum hydride (720 mL of a 3.4M solution in toluene, 2.45 mmol) in anhydrous diethyl ether (6 mL) cooled to -2° C. under a nitrogen atmosphere was added dropwise an ethereal solution (25 mL) of 4,4,4-trifluoro-3-hydroxy-3-methyl-1-[4-(1-pyrrolidinylsulfonyl)phenyl]but-1-yne (500 mg). The rate of addition was adjusted such that the reaction temperature (internal) did not exceed 10° C. Upon complete addiron the reaction was kept near 0° C. After 30 minutes the reaction was quenched by the addition of 3M sulfuric acid (20 mL). The product was extracted into diethyl ether. The combined organic extracts were dried, filtered, and evaporated. The crude product was adsorbed onto silica gel and purified by chromatography (1:8 diethyl ether: chloroform) to yield a white compound (447 mg). This material was further purified by recrystalization employing diethyi ether:hexanes (1:5) to provide the title compound (251 mg); mp 119°-121° C.; MS: m/z=350(M+1); NMR: (CDCl3): 1.59 (s,3), 1.73-1.78 (m,4), 2.45 (s,1), 3.22-3.27 (m,4), 6.41 (d,1, J=16.0), 6.93 (d,1,J=16.0), 7.52-7.55 (m,2), 7.77-7.81 (m,2). Analysis for C15H18F3NO3S: Calculated: C, 51.57; H, 5.19; N, 4.01; Found: C, 51.45; H, 5.19; N, 3.90.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[C:8]([OH:10])=O.S(Cl)([Cl:13])=O>CN(C)C=O.C1(C)C=CC=CC=1>[ClH:13].[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[C:8]([Cl:1])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: Cc1[nH]cnc1C(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1[nH]cnc1C(=O)Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a suspension of 880 g (5.4 moles) of 5-methyl-4-imidazolecarboxylic acid hydrochloride in 100 ml of dimethylformamide and 2 liters of toluene at 60° C., there was added slowly over 2 hours 790 ml (10.8 moles) of thionyl chloride. At the end of the addition, the mixture was held with good stirring for 1 hour at 80° C. It was allowed to cool, filtered, the solid was washed with 1 liter of toluene. 685 g of 5-methyl-4-imidazolecarbonyl chloride hydrochloride were obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[Cu](C#N)[C:13]#[N:14]>CN(C=O)C.C(OCC)(=O)C>[O:9]=[C:7]1[NH:6][C:5]2[CH:10]=[CH:11][C:2]([C:13]#[N:14])=[CH:3][C:4]=2[O:8]1
Reactant: N#C[Cu]C#N
Reactant: O=c1[nH]c2ccc(Br)cc2o1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]c(=O)oc2c1

Procedure:
A mixture of 6-bromo-3H-benzooxazol-2-one (47) (400 mg, 1.87 mmol, 1 eq), copper cyanide (3.3 g, 37 mmol, 20 eq), in DMF (10 ml) was stirred at 175° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, filtered to remove the precipitated solid material, and the organic phase was washed with water, purified by flash chromatography to give 2-oxo-2,3-dihydro-benzooxazole-6-carbonitrile (48).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH:12]([OH:17])[CH2:13][CH2:14][CH2:15][OH:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:18]([Si:21](Cl)([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19].C(OCC)(=O)C>O1CCCC1.O>[CH2:3]([O:10][CH2:11][CH:12]([OH:17])[CH2:13][CH2:14][CH2:15][O:16][Si:21]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:18]([CH3:20])[CH3:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCCCC(O)COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)[Si](OCCCC(O)COCc1ccccc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.96 g of sodium hydride (60 wt % in oil) was added to a solution of 5.0 g of 5-(benzyloxy)pentane-1,4-diol in 50 mL of tetrahydrofuran in a nitrogen atmosphere at a temperature of 5° C. to 10° C., and the obtained mixture was then stirred at room temperature for 30 minutes. Thereafter, 5.3 mL of triisopropylsilyl chloride was added dropwise to the reaction mixture at a temperature of 5° C. to 10° C. The reaction mixture was stirred at room temperature for 1 hour, and it was then added to a mixture of 100 mL of ethyl acetate and 100 mL of water. The organic layer was fractionated. The obtained organic layer was successively washed with 100 mL of a saturated sodium hydrogen carbonate aqueous solution, 100 mL of water and 100 mL of a saturated sodium chloride aqueous solution, and it was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/hexane=1/5 to 1/5), so as to obtain 5.4 g of 1-benzyloxy-5-((triisopropyl)silyloxy)pentan-2-ol in the form of a colorless oily product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][C:3]=1[CH3:18].CC(O)C.[OH-].[Na+].Cl>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1cc2c(cc1Br)C(=O)C1(CCC(=O)CC1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1Br)C(=O)C1(CCC(O)CC1)C2
Temperature: 25 °C
Yield: 98 %

Procedure:
6′-Bromo-5′-methylspiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione (Intermediate 2, 1.38 g, 4.49 mmol) and propan-2-ol (16.6 mL, 215 mmol) were heated to 75° C. Ground NaOH (0.176 g, 4.40 mmol) was added. The resulting mixture was heated at reflux for 1.5 h and was then allowed to cool to r.t. The mixture was concentrated to half the volume and then water (15 mL) and toluene (15 mL) were added together with 6 M aq. HCl (0.749 mL, 4.49 mmol). The layers were separated and the aqueous layer was re-extracted with toluene (15 mL). The combined organic layers were dried over Na2SO4, concentrated and dried in vacuo to afford 1.36 g (98% yield) of the title compound as a mixture of isomers (˜70:30 mixture of isomers with the hydroxyl group in equatorial and axial position) and this mixture was used in the next step without further purification: MS (ES+) m/z 308, 311 [M+H]+.
Reaction SMILES: C([S:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16])(=O)C.O>S(=O)(=O)(O)O.O.CO>[N+:15]([C:7]1[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]=1[CH2:5][SH:4])([O-:17])=[O:16]
Reactant: CC(=O)SCc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(CS)c([N+](=O)[O-])c1
Yield: 98.5 %

Procedure:
A stirred suspension of S-(2,4-dinitrobenzyl) thioacetate 16b (8.2 g, 32 mmol) in concentrated sulfuric acid--water (1:1 v/v; 14.08 cm3) and methanol (128 cm3) was heated, under reflux, for 1.5 h. The cooled products were poured into water (300 cm3) and the resulting mixture was extracted with ether (2×400 cm3). The combined organic extracts were washed with water (300 cm3), dried (MgSO4) and evaporated under reduced pressure to give 2,4-dinitrobenzyl mercaptan 17b as a yellow oil (6.75 g, 98 %) (Found: M+ =214.0084 12 C11H614N216O432S requires: 214.0048); δH [CDCl3 ] 2.21 (1 H, t, J 8.7), 4.10 (2 H, d, J 8.7), 7.75 (1 H, d, J 8.7), 8.44 (1 H, dd, J 2.4 and 8.5), 8.77 (1 H, d, J 2.4); δC [CDCl3 ] 26.2, 121.0, 127.8, 133.0, 143.6, 146.9, 148.0.
Reaction SMILES: [OH:1][CH:2]([C:14]([F:17])([F:16])[F:15])[CH2:3][CH:4]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[O:5]1.[N+:18]([O-])([O-:20])=[O:19].[Na+]>FC(F)(F)C(O)=O>[OH:1][CH:2]([C:14]([F:17])([F:15])[F:16])[CH2:3][CH:4]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([N+:18]([O-:20])=[O:19])[CH:12]=[CH:13][C:6]=2[O:5]1
Reactant: OC(CC1CCc2ccccc2O1)C(F)(F)F
Reactant: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc2c(c1)CCC(CC(O)C(F)(F)F)O2
Temperature: 0 °C

Procedure:
A solution of 8.5 g (35 mmol) of 2-(2-hydroxy-3,3,3-trifluoropropyl)-3,4-dihydro-2H-1-benzopyran in 106 ml of trifluoroacetic acid is treated with 7.4 g (88 mmol) of sodium nitrate at -10° C. The mixture is allowed to react for 45 min, then poured into ice water and the product is extracted with dichloromethane. The organic phase is then dried over sodium sulfate and concentrated under reduced pressure. By chromatography of the residue on a silica column using dichloromethane, 5.0 g of product are obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:8]3[CH2:9][CH2:10][CH2:11][C@@H:12]([C:13]4[N:17]5[CH:18]=[CH:19][N:20]=[C:21]([NH:22][CH2:23][C:24]6[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=6[O:32][CH3:33])[C:16]5=[C:15]([C:34]5[CH:43]=[CH:42][C:37]([C:38]([O:40]C)=[O:39])=[CH:36][CH:35]=5)[N:14]=4)[C:7]3=[N:6][N:5]=2)[CH2:3][CH2:2]1.O[Li].O.Cl>C1COCC1.CO.O>[CH:1]1([C:4]2[N:8]3[CH2:9][CH2:10][CH2:11][C@@H:12]([C:13]4[N:17]5[CH:18]=[CH:19][N:20]=[C:21]([NH:22][CH2:23][C:24]6[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=6[O:32][CH3:33])[C:16]5=[C:15]([C:34]5[CH:43]=[CH:42][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=5)[N:14]=4)[C:7]3=[N:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(-c2nc([C@@H]3CCCn4c(C5CC5)nnc43)n3ccnc(NCc4ccc(OC)cc4OC)c23)cc1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNc2nccn3c([C@@H]4CCCn5c(C6CC6)nnc54)nc(-c4ccc(C(=O)O)cc4)c23)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a solution of (S)-methyl 4-(3-(3-cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-8-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrazin-1-yl)benzoate (300 mg, 0.51 mmol) in THF/MeOH/H2O (3 mL/3 mL/1 mL) was added LiOH.H2O (109 mg, 2.6 mmol). The mixture was stirred at RT overnight. After the reaction was completed, the reaction mixture was acidified by 2M HCl to pH=5˜6 and extracted with EA and water. The organic layer was dried and concentrated to give (S)-4-(3-(3-cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-8-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrazin-1-yl)benzoic acid (130 mg, yield 45%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:7][CH:6]=1.Cl[C:19]1[N:24]=[C:23]([C:25](=[C:28]2[NH:32][C:31]([CH2:33][CH3:34])=[CH:30][S:29]2)[C:26]#[N:27])[CH:22]=[CH:21][N:20]=1>C(#N)C>[CH2:33]([C:31]1[NH:32][C:28](=[C:25]([C:23]2[CH:22]=[CH:21][N:20]=[C:19]([O:3][CH2:4][C:5]3[CH:6]=[CH:7][C:8]([CH2:9][N:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)=[CH:16][CH:17]=3)[N:24]=2)[C:26]#[N:27])[S:29][CH:30]=1)[CH3:34]
Reactant: CCC1=CSC(=C(C#N)c2ccnc(Cl)n2)N1
Reactant: OCc1ccc(CN2CCOCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCC1=CSC(=C(C#N)c2ccnc(OCc3ccc(CN4CCOCC4)cc3)n2)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (99 mg, 2.27 mmol) in ACN (4 mL) was added a solution of N-(4-hydroxymethylbenzyl)morpholine 313 mg, 1.51 mmol) in ACN (4 mL). The mixture was stirred 1 h at rt. Then (2-chloropyrimidin-4-yl)(4-ethyl-1,3-thiazol-2(3H)-ylidene)acetonitrile (200 mg, 0.76 mmol) was added portion wise. The resulting mixture was heated up at 80° C. for 5 h. After cooling down to rt the ACN was evaporated. EtOAc (5 mL) was added to the residue. After one night at 4° C., the yellow solid was filtered off affording the title compound as a free base (HPLC (max plot) 73.9%). The solid was taken up in DCM and excess TFA then ether were added. The precipitate formed was filtered off, washed with ether (3×) then dried under reduced pressure at 40° C. overnight, affording 409 mg of the title compound as a diTFA salt (Yellow powder, Y=81.1%)
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=O)[NH:12][C:13]4[N:14]([N:16]=[CH:17][N:18]=4)[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:11]1[C:10]2[CH:9]=[N:8][C:7]3[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=3[C:15]=2[N:14]2[N:16]=[CH:17][N:18]=[C:13]2[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1ncc2c1ncc1c(=O)[nH]c3ncnn3c12
Product: CCn1ncc2c1ncc1c(Cl)nc3ncnn3c12
Yield: 92 %

Procedure:
25.5 g. of 8-ethyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one (0.1 mol.) are refluxed in 100 ml. of phosphorus oxychloride for 12 hours. After this time, the excess phosphorus oxychloride is distilled off in vacuo, the residue is treated with dry acetone and filtered off. 25 g. of 5-chloro-8-ethyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine are obtained, yield 92%; m.p. 196°-197°.