Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[CH:7]=1.[CH3:27][C:28]1([O:31][CH2:30]1)[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:9]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:10][N:11]([CH2:27][C:28]([OH:31])([CH3:30])[CH3:29])[N:12]=2)[CH:7]=1
Reactant: CC1(C)CO1
Reactant: COc1ccc(Cl)cc1-c1[nH]ncc1NC(=O)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(CC(C)(C)O)cc1NC(=O)c1cnn2cccnc12
Temperature: 40 °C
Reaction time: 15 h
Yield: 40.1 %

Procedure:
To a solution of N-(5-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (102.7 mg, 0.279 mmol) in 3 mL, DMF was added isobutylene oxide (0.20 mL, 2.2 mmol) and cesium carbonate (180.0 mg, 0.5524 mmol). The reaction was stirred at 40° C. for 15 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 49.3 mg (40%) of N-(3-(5-chloro-2-methoxyphenyl)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=441.1; 1H NMR (400 MHz, DMSO-d6) δ: 9.68 (s, 1H), 9.32 (dd, 1H), 8.76 (d, 1H), 8.64 (s, 1H), 8.30 (s, 1H), 7.48 (dd, 1H), 7.39 (d, 1H), 7.31 (s, 1H), 7.28 (t, 1H), 4.72 (s, 1H), 4.07 (s, 2H), 3.84 (s, 3H), 1.12 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][NH:11][N:10]=1.N#N.C(N(CC)CC)C.[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][N:11]([C:31](=[O:34])[CH2:32][CH3:33])[N:10]=1
Reactant: COc1ccc2c(c1)CNN=C2Cc1c(Cl)cncc1Cl
Reactant: CCC(=O)Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)N1Cc2cc(OC)ccc2C(Cc2c(Cl)cncc2Cl)=N1
Reaction time: 3 h
Yield: 85.3 %

Procedure:
A solution of 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-1,2-dihydro-phthalazine (1 g, 3.1 mmoles), prepared as described in example 22, in THF (35 ml), under stirring and dry N2 at room temperature, was dropwise added with triethylamine (1.08 ml, 7.76 mmoles), then, at 0° C., with propionyl chloride (0.323 ml, 3.72 mmoles). After 10 minutes the mixture was brought to room temperature and after 3 hours poured into water/ice and THF was evaporated. The mixture was extracted more times with CH2Cl2 and the organic phases were washed with 5% NaOH and water, anhydrified and brought to dryness to give a solid which was crystallised from acetonitrile (50 ml). 1 g of the title compound was obtained (yield: 86%). m.p.: 195-197° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10](O)[CH3:11])=[CH:6][CH:5]=1.C(Br)(Br)(Br)[Br:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:16][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=1)[CH3:11]
Reactant: BrC(Br)(Br)Br
Reactant: CC(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(Br)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(4-(trifluoromethoxy)phenyl)ethanol (150 mg; 0.72 mmol) in anh. DCM (5 ml) was treated at rt with CBr4 (241 mg; 0.72 mmol), and with PPh3 (190 mg; 0.72 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 16 h. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 1-(1-bromoethyl)-4-(trifluoromethoxy)benzene as a colorless oil which was directly used for the next reaction.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[OH:14][C:15]1[CH:20]=[C:19]([CH:21]([CH3:26])[CH2:22][CH2:23][CH:24]=O)[O:18][C:17](=[O:27])[C:16]=1[C:28](=[O:31])[CH2:29][CH3:30]>C1COCC1>[OH:14][C:15]1[CH:20]=[C:19]([CH:21]([CH3:26])[CH2:22][CH2:23]/[CH:24]=[CH:7]/[C:5]([O:4][CH3:3])=[O:6])[O:18][C:17](=[O:27])[C:16]=1[C:28](=[O:31])[CH2:29][CH3:30]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CCC(=O)c1c(O)cc(C(C)CCC=O)oc1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(=O)c1c(O)cc(C(C)CC/C=C/C(=O)OC)oc1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaH (0.06 g; 1.5 mmol; 60% dispersion in mineral oil; Aldrich) was added to trimethyl phosphonoacetate (0.190 g; 1.0 mmol; Aldrich) in 10 ml THF. The reaction mixture was stirred at 25° C. for 15 min, after which 4-(4-hydroxy-2-oxo-3-propionyl-2H-pyran-6-yl)pentanal (VI; 0.124 g; 0.5 mmol) in 10 ml THF was added. The reaction mixture was stirred at 25° C. for 4 h, quenched with saturated NH4Cl, extracted with 3×20 ml EtOAc, dried with anhydrous Na2SO4, and evaporated. The product was purified via silica flash chromatography (40% EtOAc in hexanes).
Reaction SMILES: [CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.Br[C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N+:23]([C:20]1[N:21]=[CH:22][C:17]([N:3]2[CH2:4][CH:5]3[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:1]([CH2:7][CH2:6]3)[CH2:2]2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc([N+](=O)[O-])nc1)C2
Temperature: 140 °C

Procedure:
tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.4 g; 1.9 mmol), prepared as described in (J. Med. Chem., (1998) 41, 674), 5-bromo-2-nitropyridine (0.43 g; 2.27 mmol), prepared as described in (J. Am. Chem. Soc., (1945) 67, 668), and triethylamine (0.23 g; 2.27 mmol) in toluene (10 mL) were heated at reflux for 14 hours. After evaporation of the solvent, additional triethylamine (0.23 g) was added and the mixture further heated at 140° C. for 2 hours. The residue was purified on SiO2 (CH2Cl2:EtOAc 9:1) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:10]2([CH3:11])[CH:5]([C:6](=[O:12])[CH2:7][CH2:8][CH2:9]2)[CH2:4][CH:3]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20].[CH3:24][Si:25]([CH3:28])([CH3:27])Cl.N1C=CN=C1.N1C=CC=CC=1>C(OCC)C>[CH3:1][C:2]1([CH3:23])[C:10]2([CH3:11])[CH:5]([C:6](=[O:12])[CH2:7][CH2:8][CH2:9]2)[CH2:4][CH:3]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:21])([O:22][Si:25]([CH3:28])([CH3:27])[CH3:24])[CH3:20]
Reactant: CC(C)(O)CCCOCCC1CC2C(=O)CCCC2(C)C1(C)C
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(CCCOCCC1CC2C(=O)CCCC2(C)C1(C)C)O[Si](C)(C)C
Yield: 78.9 %

Procedure:
201 mg (0.62 mmol) of 50 is reacted with 205 mg (1.86 mmol) of trimethylchlorosilane, 167 mg (2.42 mmol) of imidazole and 0.25 ml of pyridine in 15 ml of diethyl ether analogously to 33., and 194 mg of the title compound is obtained as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([C:14]2[S:21][C:20]([CH3:22])=[C:19]3[C:15]=2[CH2:16][C@H:17]2[C:23]([CH3:25])([CH3:24])[C@H:18]23)=[O:13])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].Br[CH2:27][CH2:28][OH:29]>C(O)(C)C.[OH-].[Na+]>[OH:29][CH2:28][CH2:27][O:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([CH2:10][CH2:11][C:12]([C:14]2[S:21][C:20]([CH3:22])=[C:19]3[C:15]=2[CH2:16][C@H:17]2[C:23]([CH3:25])([CH3:24])[C@H:18]23)=[O:13])=[CH:5][C:6]=1[CH3:9]
Reactant: OCCBr
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCCO
Temperature: 70 °C
Reaction time: 5.5 h
Yield: 46.6 %

Procedure:
A solution of 3-(3,5-dimethyl-4-hydroxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (3.00 g, 8.46 mmol, Intermediate 10) in isopropanol (80 mL) and 2 N aq. NaOH (30 mL) is treated with 2-bromoethanol (2.11 g, 16.9 mmol). The dark red reaction mixture is stirred at 70° C. for 5.5 h. The solvent is removed under reduced pressure and the residue is dissolved in EA and washed twice with water. The organic layer is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 1:1 to give 3-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (1.57 g) as an orange oil; LC-MS: tR=1.09 min, [M+1]+=399.35.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[CH:21]=[C:20]([C:22]4([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:24][CH:23]4[Si](C)(C)C)[CH:19]=[CH:18][C:16]=3[N:17]=2)=[C:9]([F:35])[CH:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[CH:21]=[C:20]([C:22]4([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH2:23][CH2:24]4)[CH:19]=[CH:18][C:16]=3[N:17]=2)=[C:9]([F:35])[CH:8]=1
Reactant: C[Si](C)(C)C1CC1(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)cc2s1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
In a reactor bottle were combined 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-(1-phenyl-2-(trimethylsilyl)cyclopropyl)benzo[d]thiazole (1.305 g, 2.6 mmol) and neat tetrabutylammonium fluoride (25 mL, 25 mmol). The reaction mixture was heated to 110° C. in an oil bath and allowed to stir for 2 h. The mixture was cooled and extracted with EtOAc and water, dried over MgSO4 and concentrate in vacuo. Purification by silica gel chromatography afforded 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-(1-phenylcyclopropyl)-benzo[d]thiazole. MS (ESI) m/z: Calculated: 431.1; Observed: 432.1 (M++1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[OH-].[Na+].C1(C)C=CC=CC=1>O>[C:1]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1ccccc1)N1CCCCC1
Yield: 95 %

Procedure:
Benzoyl chloride (500 mL, 606 g, 4.3 mol) was added dropwise to a rapidly stirring mixture of piperidine (426 mL 367 g, 4.3 mol), sodium hydroxide (190 g, 4.7 mol, 1.1 equivalents), toluene (1 L), and water (1.7 L) over a period of 70 minutes. After the addition was complete, the mixture was stirred at 25° C. for one hour. The organic and aqueous phases were separated, and the organic phase was washed with 2N hydrochloric acid (2×100 mL), concentrated by rotary evaporation, and distilled under vacuum to yield benzoylpiperidine as a colorless liquid which crystallized on standing. (779 g, 95% yield, bp 169° C. to 171° C.).
Reaction SMILES: O=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8](F)[CH:7]=1)[CH2:3][C:4]#[N:5].[NH2:13][C:14]([NH2:16])=[S:15].II>N1C=CC=CC=1>[NH2:16][C:14]1[S:15][C:3]([C:4]#[N:5])=[C:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:13]=1
Reactant: N#CCC(=O)c1cccc(F)c1
Reactant: NC(N)=S
Agent: II
Solvent: c1ccncc1
Product: N#Cc1sc(N)nc1-c1ccccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 102.3 %

Procedure:
5 g (34.0 mmol) of 3-oxo-3-(3-fluorophenyl)-propanenitrile were dissolved in pyridine (30 ml) and thiourea (5 g, 68.0 mmol) and iodine (8.70 g, 34.40 mmol) were added successively. The solution was stirred at 100° C. for 12 h. The mixture was then cooled to room temperature and poured into ice-water (500 ml). The resulting solid was filtered, washed with water and recrystallized from ethanol to give 7.0 g (91%) of a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:14]([O-])=O)[CH2:6]1)=[O:4].[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:14])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1Cc2cccc([N+](=O)[O-])c2C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1Cc2cccc(N)c2C1
Yield: 9.8 %

Procedure:
A mixture of methyl-4-nitroindane-2-carboxylate (2.4 g, 0.11 mol) and 10% palladium on carbon (1.1 g, 0.01 mol) in ethyl acetate (15 mL) was shaken under 55 PSI hydrogen for 1 hour. It was then filtered and the filtrate was concentrated to give 2.07 g white solid (100%).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH3:10])=[O:4].[Li]CCCC.C1COCC1.C(#N)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>C1COCC1>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:1]2[NH:2][C:3](=[O:4])[C:5]3[CH:9]=[CH:8][S:7][C:6]=3[CH:10]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(C#N)cc1
Reactant: CNC(=O)c1ccsc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3sccc3c(=O)[nH]2)cc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
To a solution of N-methyl-2-methylthiophene-3-carboxamide (36.0 g) in THF (500 ml) was added dropwise 2.5M n-BuLi/THF solution (200 ml) at −70° C. The reaction solution was stirred at −70° C. for 2 hr, followed by the addition of anisonitrile (31.0 g) at once. After the dry ice/acetone bath was removed, the reaction mixture was back to room temperature. Three hours later, an aqueous solution of saturated ammonium chloride and ether were added thereto, and then the mixture was further stirred for 1 hr. The resulting white precipitates were collected by filtration, washed with water, ether and n-hexane in this order, and then dried, to give the title compound (17.9 g, yield; 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=2)[N:10]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[CH:9]=1.[OH-].[Na+].O.Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)[N:10]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[CH:9]=1
Reactant: COC(=O)c1ccc2c(-c3ccccc3Cl)cn(-c3ccc(C)cc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-n2cc(-c3ccccc3Cl)c3ccc(C(=O)O)cc32)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
To a solution of methyl 3-(2-chlorophenyl)-1-(4-methylphenyl)-1H-indole-6-carboxylate (0.11 g, 0.28 mmol) in tetrahydrofuran (2.8 mL) was added sodium hydroxide (2.0 M; 1.40 mL, 2.80 mmol). Water (1.5 mL) was added and the mixture was stirred at 50° C. After 18 h, the mixture was cooled to ambient temperature and 1.0 M hydrochloric acid was added until pH<3. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with saturated aqueous sodium chloride (1×10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (98 mg): LC-MS [M+1]=362.1.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:34]1([CH2:39][CH2:40][CH2:41]O)[CH2:38][CH2:37][CH2:36][CH2:35]1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:41][CH2:40][CH2:39][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: COc1cc2c(Cl)cnnc2cc1O
Reactant: OCCCN1CCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)cnnc2cc1OCCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.5 %

Procedure:
To a solution of 4-chloro-7-hydroxy-6-methoxycinnoline (300 mg, 1.42 mmol), triphenylphosphine (747 mg, 2.85 mmol) and 3-(pyrrolidin-1-yl)propan-1-ol (276 mg, 2.1 mmol) in methylene chloride (12 ml) was added diethyl azodicarboxylate (449 μl, 2.85 mmol) dropwise and the mixture was stirred for 2 hours at ambient temperature. The volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride/methanol (90/10) followed by methylene chloride/methanol/methanol saturated with ammonia (89/10/1 followed by 85/10/5). The fractions containing the expected product were combined and evaporated to give 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)cinnoline (80 mg, 18%).
Reaction SMILES: [Br:1]Br.[O:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]1[N:12]1[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH2:14][CH2:13]1.C([O-])(=O)C.[Na+]>O.C(O)(=O)C>[Br:1][C:9]1[CH:10]=[C:11]2[O:3][C:4]([N:12]3[CH:18]4[CH2:17][CH2:16][N:15]([CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[N:5][C:6]2=[N:7][CH:8]=1
Reactant: c1cnc2nc(N3CCN4CCC3CC4)oc2c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Brc1cnc2nc(N3CCN4CCC3CC4)oc2c1

Procedure:
Bromine (0.12 mL, 2.29 mmol) was added to a solution of 4-oxazolo[4,5-b]pyridin-2-yl-1,4-diaza-bicyclo[3.2.2]nonane (560 mg, 2.29 mmol, prepared in Example 27) and sodium acetate (2.26 g, 27.5 mmol) in water (12 mL) and acetic acid (12 mL). The resulting mixture was heated to reflux for 2 h. The mixture was cooled and extracted with ethyl acetate (3×). The combined organic layers were washed with water (2×) and brine (1×) and dried over sodium sulfate, filtered and concentrated. The crude residue was purified by chromatography (Biotage, 25M) using a gradient elution from 4% MeOH/CDCl3 containing 0.1% NH4OH to 8% MeOH/CDCl3 containing 0.1% NH4OH giving 578 mg (78%) of the title compound as an oil: 1H NMR CDCl3, 400 MHz) δ 8.23 (d, 1H, J=1.7 Hz), 7.50 (d, 1H, J=1.7 Hz), 4.51 (br s, 1H), 3.92 (br s, 2H), 3.16-3.04 (m, 4H), 3.02-2.94 (m, 2H), 2.17-2.01 (m, 2H), 1.83-1.74 (m, 2); MS (Cl) m/z 325.0/323.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[S:25]1[C:29]([CH:30]=O)=[CH:28][C:27]2[CH:32]=[CH:33][CH:34]=[CH:35][C:26]1=2>>[S:25]1[C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[CH:28]=[C:29]1[CH2:30][NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:7]2[C:6]3[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[N:10]=[N:9][C:8]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: O=Cc1cc2ccccc2s1
Product: Clc1cccc2c(-c3cccc(NCc4cc5ccccc5s4)c3)c(-c3ccccc3)nnc12

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and benzo[b]thiophene-2-carbaldehyde according the procedure of Example 5 Step 5. MS (ES) m/z 478.1.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH2:21][CH3:22])[CH:15]=[CH:14][C:13]=1[OH:23])[CH3:8].CI>CN(C)C=O>[CH2:7]([O:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH2:21][CH3:22])[CH:15]=[CH:14][C:13]=1[O:23][CH3:1])[CH3:8]
Reactant: CCOCOc1ccc(O)c(OCOCC)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOCOc1ccc(OC)c(OCOCC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.9 %

Procedure:
Potassium carbonate (14.3 g, 103 mmol) was added to 3a (2.50 g, 10.3 mmol) in N,N-dimethylformamide (103 mL). After 10 minutes, methyl iodide (6.43 mL, 103 mmol) was added and the solution was heated to reflux for 12 hours. Upon cooling to room temperature, the solution was extracted with EtOAc (3×50 mL); combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), and concentrated. The residue was purified by column chromatography (SiO2, 4:1 Hexane:EtOAc) to afford 4a as a yellow oil (2.40 g, 91%): 1H NMR (CDCl3, 500 MHz) δ 6.87 (d, J=2.8 Hz, 1H), 6.72 (d, J=8.9 Hz, 1H), 6.60 (dd, J=13.3, 1.7 Hz, 1H), 5.18 (s, 2H), 5.07 (s, 2H), 3.76 (s, 3H), 3.72-3.69 (m, 2H), 3.68-3.63 (m, 2H), 1.17-1.13 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 150.7, 146.2, 143.9, 111.2, 107.9, 105.8, 93.2, 93.0, 63.3, 63.0, 55.4, 14.1, 14.0; IR (film) νmax 2976, 2932, 2899, 2835, 1595, 1508, 1393, 1227, 1153, 1103, 1080, 1009, 847 cm−1; HRMS (ESI+) m/z: [M+Na]+ calcd for C13H20O5, 279.1208; found, 279.1181.
Reaction SMILES: [CH3:1][C:2]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:16]([O-])([O-:18])=[O:17].[K+]>OS(O)(=O)=O>[CH3:10][C:2]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])([CH3:1])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N+:16]([O-:18])=[O:17])=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])[O-]
Reactant: CCC(=O)NC(C)(C)Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCC(=O)NC(C)(C)Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 55 %

Procedure:
To H2SO4(20 ml) at 0-10° C. N-(1,1-dimethyl-2-phenyl-ethyl)-propionamide was slowly added. The mixture was stirred until a clear solution was obtained. Then KNO3 (750 mg, 7.42 mmol) was added in portions at 0-5° C. The mixture was stirred at room temperature for 16 h after which it was poured into ice water. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with NaOH, water and brine, dried over MgSO4, filtered, and the solvent evaporated under reduced pressure to give the product as a brown oil (1 g, 55%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:15]=[CH:14]3)[CH2:6][CH2:5]1.N1C=CN=C1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CN(C=O)C>[Si:32]([O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:15]=[CH:14]3)[CH2:6][CH2:5]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)n1ccc2cc(CN3CCN(CCO)CC3)ccc21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ccc2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc21
Yield: 90 %

Procedure:
In a similar manner to Step 1 of Reference Example 18, 5-[4-(2-hydroxyethyl)-1-piperazinylmethyl]-1-(tert-butoxycarbonyl)indole (5.02 g, 14.0 mmol) was dissolved in DMF (50 mL), and the solution was treated with imidazole (1.43 g, 21.0 mmol) and tert-butyldimethylsilyl chloride (3.16 g, 21.0 mmol) to obtain 5-(4-[2-(tert-butyldimethylsilyloxy)ethyl]-1-piperazinylmethyl)-1-(tert-butoxycarbonyl)indole (5.97 g, yield 90%).