Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[S:23]1[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24]1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:28][C:25]4[CH:26]=[CH:27][S:23][CH:24]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: O=Cc1ccsc1
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4ccsc4)c23)c1

Procedure:
Analogously to Example 32, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 180 mg of acetic acid are dissolved in 26 ml of methanol and reacted with 168 mg (1.5 mmol) of thiophene-3-carbaldehyde to form 4-(3-chloro-phenylamino)-3-[(thien-3-yl)-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of that intermediate in 15 ml of DMEU with 8 ml (8 mmol) of DIBAL-H, analogous working-up and digestion in DIPE yield 4-(3-chlorophenylamino)-3-[(thien-3-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100/20)=11.4; FAB-MS: (M+H)+=357.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][CH:9]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-])=O>[Pd].C(OCC)(=O)C.CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[C:16]([O:18][CH:19]([CH3:20])[CH3:21])=[O:17])=[CH:22][CH:23]=1
Reactant: CC(C)OC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)C(Cc1ccc(N)cc1)C(=O)OC(C)C
Reaction time: 2.5 h
Yield: 31.5 %

Procedure:
A 100-mL round bottom flask was charged with diisopropyl 2-(4-nitrobenzyl)malonate (1.19 g, 3.68 mmol) and 10% palladium on carbon (0.30 g) in 1:1 ethyl acetate/methanol (20 mL). This mixture was vigorously stirred under H2 (1 atm) for 2.5 h. After this time, the mixture was filtered through celite and purified by chromatography on silica eluting with hexanes/ethyl acetate (10:1 to 0:10) to afford the title compound (0.34 g, 32%) as a white solid. MW=293.36. 1H NMR (DMSO-d6, 500 MHz) δ 6.83 (d, J=7.5 Hz, 2H), 6.44 (d, J=7.0 Hz, 2H), 4.91-4.82 (m, 4H), 3.55 (t, J=8.0 Hz, 1H), 2.86 (d, J=8.0 Hz, 2H), 1.14 (d, J=6.0 Hz, 6H), 1.11 (d, J=8.0 Hz, 6H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:12])=[CH:7][CH:8]=[C:9]([F:11])[CH:10]=2)[CH2:3][CH2:2]1.[F:13][C:14]([F:27])([F:26])[C:15]([C:18]1[CH:19]=[C:20]([CH:24]=O)[CH:21]=[N:22][CH:23]=1)([OH:17])[CH3:16].OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[CH:1]1([N:4]2[C:5]3[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=3[N:12]=[C:24]2[C:20]2[CH:19]=[C:18]([C:15]([OH:17])([CH3:16])[C:14]([F:27])([F:13])[F:26])[CH:23]=[N:22][CH:21]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(F)cc1NC1CC1
Reactant: CC(O)(c1cncc(C=O)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(O)(c1cncc(-c2nc3ccc(F)cc3n2C2CC2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound from Step E (0.058 g, 0.35 mmol) in DMF (1.68 mL) and water (0.06 mL) were added the title compound from Step C (0.076 g, 0.35 mmol) and OXONE® (0.139 g, 0.226 mmol). The resulting mixture was stirred at room temperature for 1 hour, then diluted with ethyl acetate and water. Solid potassium carbonate was added until the aqueous layer was basic (pH ˜9). Ethyl acetate was then added, and the organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography on silica gel (10% acetone in dichloromethane, then 30% acetone in dichloromethane) provided the title compound as a racemic mixture. That racemic mixture was then separated into two enantiomers by HPLC (ChiralCel AS column, 25% MeOH (0.2% DEA)/CO2, 70 mL/min, 100 bar, 35° C.). Data for EXAMPLE 6 (Enantiomer A): LCMS m/z 365.99 [M+H]+; 1 H NMR (500 MHz, CDCl3) δ 9.14 (s, 1 H), 8.85 (s, 1 H), 8.59 (s, 1 H), 7.76 (dd, J=8.8, 4.8 Hz, 1 H), 7.30 (dd, J=8.5, 2.1 Hz, 1 H), 7.11-7.07 (m, 1 H), 4.85 (br s, 1 H), 3.55-3.53 (m, 1 H), 1.79 (s, 3 H), 1.22-1.12 (m, 2 H), 0.80-0.72 (m, 2 H). Data for Example 7 (Enantiomer B): LCMS m/z 365.97 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.16 (s, 1 H), 8.88 (s, 1 H), 8.57 (s, 1 H), 7.76 (dd, J=8.8, 4.8 Hz, 1 H), 7.30 (dd, J=8.5, 2.0 Hz, 1 H), 7.10-7.05 (m, 1 H), 3.91 (br s, 1 H), 3.56-3.55 (m, 1 H), 1.84 (s, 3 H), 1.18-1.15 (m, 2 H), 0.80-0.71 (m, 2 H).
Reaction SMILES: O.[OH-].[Li+].O.C([O:7][C:8]([C:10]1[CH:11]=[N:12][N:13]([C:15]2[NH:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][C:19]4[O:29][CH2:28][CH2:27][O:26][C:20]=4[CH:21]=3)[N:16]=2)[CH:14]=1)=[O:9])C>C1COCC1>[O:25]=[C:23]1[C:22]2[C:17](=[CH:18][C:19]3[O:29][CH2:28][CH2:27][O:26][C:20]=3[CH:21]=2)[N:16]=[C:15]([N:13]2[CH:14]=[C:10]([C:8]([OH:9])=[O:7])[CH:11]=[N:12]2)[NH:24]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc4c(cc3c(=O)[nH]2)OCCO4)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnn(-c2nc3cc4c(cc3c(=O)[nH]2)OCCO4)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
Lithium hydroxide monohydrate (28.7 mg, 0.684 mmol) and water (0.29 mL) were added to 1-(4-oxo-3,4,7,8-tetrahydro-[1,4]dioxino[2,3-g]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (78.0 mg, 0.228 mmol) in THF (0.85 mL). The reaction mixture was stirred at room temperature for 18 h and was then concentrated and the residue re-dissolved in water (5 mL). This solution was brought to pH 1 with 1M aqueous HCl. The resulting precipitate was collected and dried to yield the titled compound (54.3 mg, 75% yield). MS (ESI/Cl): mass calcd. for C14H10N4O5, 314.1; m/z found, 315.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.97 (s, 1H), 12.61 (s, 1H), 8.89 (d, J=0.6 Hz, 1H), 8.23 (s, 1H), 7.48 (s, 1H), 7.14 (s, 1H), 4.46-4.29 (m, 4H).
Reaction SMILES: [H-].[Na+].[CH:3]1([SH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:10][CH2:11][CH2:12][OH:13].O>CN(C=O)C.C(OCC)C>[CH:3]1([S:8][CH2:10][CH2:11][CH2:12][OH:13])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OCCCBr
Reactant: SC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: OCCCSC1CCCC1
Temperature: 80 °C

Procedure:
To a suspension of sodium hydride (commercially available, for example, from Aldrich) (60% dispersion in mineral oil; 800 mg, 20 mmol) in dry DMF (30 ml) was carefully added cyclopentyl mercaptan (commercially available, for example, from Aldrich and/or Alfa Aesar) (2.14 ml, 20 mmol). The resultant suspension was stirred at room temperature, under nitrogen for 15 min before adding 3-bromopropanol (commercially available, for example, from Aldrich) (1.81 ml, 20 mmol). The mixture was then stirred under nitrogen and heated to 80° C. overnight. Water (20 ml) was cautiously added to the reaction mixture, followed by diethyl ether (50 ml). The aqueous solution was extracted with diethyl ether (2×50 ml). The combined organic solutions were washed with water (100 ml) and brine (100 ml) and concentrated in vacuo to leave a yellow oil, which was purified by flash chromatography on silica eluting with cyclohexane-EtOAc (3:1) increasing to (1:1). The solvents were removed in vacuo to afford the title compound (2.18 g). LCMS RT=2.61 min, ES+ve m/z 161 (M+H)+.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH2:14]([O:16][C:17]([C:19]1[CH:29]=[C:22]2[C:23]([CH2:27][OH:28])=[CH:24][CH:25]=[CH:26][N:21]2[N:20]=1)=[O:18])[CH3:15].CC(C)=O>C(O)(C)C>[CH3:15][CH2:14][O:16][C:17]([C:19]1[CH:29]=[C:22]2[C:23]([C:27]([OH:3])=[O:28])=[CH:24][CH:25]=[CH:26][N:21]2[N:20]=1)=[O:18]
Reactant: CC(C)=O
Reactant: CCOC(=O)c1cc2c(CO)cccn2n1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CCOC(=O)c1cc2c(C(=O)O)cccn2n1
Reaction time: 0.33 h

Procedure:
A 2.65 M solution of the Jones reagent (28 mL) is added dropwise over 40 min to a solution of 4-hydroxymethylpyrazolo[1,5-a]pyridine-2-carboxylic acid ethyl ester (5.30 g, 24.1 mmol) and acetone (240 mL) under air cooled by a water bath. After 20 min, isopropanol (3 mL) is added dropwise. After stirring for 30 min, the blue-green mixture is filtered (acetone rinse). The organics are concentrated under reduced pressure. The residue is dissolved in water. Et2O is added and the mixture is stirred for 15 min. The resulting solid is collected by filtration. The filtrate is dried to afford the title compound as a tan solid. LC-MS m/z (M+Na+): 257.02§.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[C:9](=[CH:12]N3CCOCC3)[CH2:8][CH2:7][C:5]=2[N:6]=1.[N+]([O-])(O)=O.[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28]([NH:31][C:32]([NH2:34])=[NH:33])=[CH:27][CH:26]=1.[OH-].[Na+]>COCCO>[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28]([NH:31][C:32]2[N:34]=[CH:12][C:9]3[CH2:8][CH2:7][C:5]4[N:6]=[C:2]([CH3:1])[S:3][C:4]=4[C:10]=3[N:33]=2)=[CH:27][CH:26]=1
Reactant: Cc1nc2c(s1)C(=O)C(=CN1CCOCC1)CC2
Reactant: COc1ccc(NC(=N)N)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O=[N+]([O-])O
Product: COc1ccc(Nc2ncc3c(n2)-c2sc(C)nc2CC3)cn1
Temperature: 100 °C
Yield: 8.1 %

Procedure:
A mixture of 2-methyl-6-morpholin-4-ylmethylene-5,6-dihydro-4H-benzothiazol-7-one (200 mg, 0.76 mmol), N-(6-methoxy-pyridin-3-yl)-guanidine nitrate (192 mg, 0.84 mmol), NaOH (34 mg, 0.84 mmol) and 2-methoxyethanol (2 mL) was heated at 100° C. for 24 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (20% EtOAc:hexane) gave the title product as a white solid (20 mg, 8%): mp 210-211° C. Anal. RP-HPLC: tR 11.6 min (10-70% MeCN, purity 93%). 1H-NMR (CDCl3): δ 8.42 (d, 1H, J 2.4, Ph-H), 8.26 (s, 1H, Py-H), 8.08 (dd, 1H, J 9.1, 2.9, Ph-H), 7.19 (brs, 1H, NH), 6.86 (d, 1H, J 9.1, Ph-H), 4.04 (s, 3H, OMe), 3.13 (m, 4H, CH2—CH2), 2.87 (s, 3H, CH3). 13C-NMR (CDCl3): δ 169.47, 159.97, 159.38, 159.12, 157.10, 155.16, 137.95, 131.90, 130.45, 128.62, 116.48, 110.33, 53.49, 25.29, 23.92, 19.84. MS (ESI+): m/z 326.08 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=O)[CH2:12][C:11](=[O:16])[CH2:10]1.C([O-])(=O)C.[NH4+:21]>C(O)C>[NH2:21][CH:13]1[CH2:14][CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:10][C:11](=[O:16])[CH2:12]1
Reactant: [NH4+]
Reactant: O=C1CC(=O)CC(c2cc(F)ccc2F)C1
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC1CC(=O)CC(c2cc(F)ccc2F)C1
Yield: 92.1 %

Procedure:
A solution of 5-(2,5-difluorophenyl)cyclohexane-1,3-dione (4.0 g) and ammonium acetate (4.1 g) in ethanol (60 ml) was heated under reflux for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with water and dried to obtain 1-amino-5-(2,5-difluorophenyl)cyclohexan-3-one (3.7 g).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[N:41][CH:40]=[CH:39][N:38]=2)[CH:34]=[CH:35][CH:36]=1.O>CN(C)C=O>[C:14]1([C:12]2[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]([CH2:8][C:7]3[CH:27]=[CH:28][C:4]([O:3][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]5[CH:42]=[N:41][CH:40]=[CH:39][N:38]=5)[CH:32]=4)=[CH:5][CH:6]=3)[CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: ClCc1cccc(-c2cnccn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccc(-c4cnccn4)c3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.4 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 2-(3-Chloromethylphenyl)pyrazine (307 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[4-phenyl-1-[4-[3-(2-pyrazinyl)benzyloxy]benzyl]-3-pyrrolyl]propionate (647 mg, yield: 83%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11].[CH2:13]([O:15][C:16](=[O:20])[CH:17](Br)[CH3:18])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[O:11][CH:17]([C:16]([O:15][CH2:13][CH3:14])=[O:20])[CH3:18]
Reactant: COC(=O)c1cc(Br)ccc1O
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(Br)cc1C(=O)OC
Yield: 100 %

Procedure:
A mixture of 5-bromo-2-hydroxy-benzoic acid methyl ester (25.0 g, 103 mmol), 2-bromo-propionic acid ethyl ester (18.6 g, 103 mmol) and potassium carbonate (50.2 g, 360 mmol) in acetone (500 mL) is heated under reflux for 24 h. The reaction mixture is filtered, and the filtrate concentrated by rotary evaporation. The residue is dissolved in dichloromethane and washed twice with water. The organic layer is dried over Na2SO4, filtered and concentrated at reduced pressure to afford the title compound as a colorless oil (34.1 g, 103 mmol, 100%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.91 (d, J=2.7 Hz, 1H), 7.49 (dd, J=8.8, 2.7 Hz, 1H), 6.75 (d, J=8.8 Hz, 1H), 4.71 (q, J=6.8 Hz, 1H), 4.20 (q, J=7.1 Hz, 2H), 3.88 (s, 3H), 1.65 (d, J=6.8 Hz, 3H), 1.23 (t, J=7.1 Hz, 3H). MS (ES+): 331 (M(C13H1579BrO5)+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH:13]=O)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClCCCl.Cl.[CH3:20][O:21][C:22](=[O:25])[CH2:23][NH2:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:4]([Si:1]([CH3:2])([CH3:3])[O:8][CH2:9][C:10]1([CH2:13][NH:24][CH2:23][C:22]([O:21][CH3:20])=[O:25])[CH2:11][CH2:12]1)([CH3:5])([CH3:6])[CH3:7]
Reactant: COC(=O)CN
Reactant: CC(C)(C)[Si](C)(C)OCC1(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)CNCC1(CO[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropanecarbaldehyde (5.0 g, 0.023 mol) in anhydrous 1,2-dichloroethane (113 mL, 1.44 mol) was added glycine methyl ester, hydrochloride (2.92 g, 0.0232 mol), TEA (6.53 mL, 0.0466 mol), and sodium triacetoxyborohydride (10.4 g, 0.0467 mol). The resulting mixture was stirred at RT for 1 h. LC/MS data indicated that the reductive amination was complete to afford methyl ({[1-({[tert-butyl-(dimethyl)silyl]oxy}methyl)cyclopropyl]methyl}amino)acetate. LC-MS: 288.2 (M+1H)+. To the crude reaction mixture was added benzaldehyde (2.8 mL, 0.028 mol), followed by a second aliquot of sodium triacetoxyborohydride (6 g). After stirring at RT for 2 h, the reaction was quenched by the addition of saturated aqueous NaHCO3. The organic layer was separated and washed with brine, then dried (MgSO4), and concentrated in vacuo. The crude product (9.1 g) was purified by Combiflash chromatography (120 g silica gel column, 0-15% EtOAc/hexanes 20 min), to afford the desired product as an oil (4.6 g). LC/MS: 378.2 (M+1H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[N:6][CH:7]=1.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].C1(C)C=CC=CC=1>ClCCl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:28]=[CH:27][CH:26]=[C:11]([CH:12]=[C:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:10]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ncc(Br)cn3)c2)CC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Brc1cnc(Oc2cccc(C=C3CCNCC3)c2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 4-(3-(5-bromopyrimidin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.285 g, 0.629 mmol) was suspended in dichloromethane (4 mL) and treated with trifluoroacetic acid (2 mL). The reaction mixture was stirred at ambient temperature for 3 h. Toluene was added and the reaction was concentrated in vacuo. After evaporating again from toluene, the residue was dried in vacuo to afford the title compound (0.385 g, quantitative yield based on 2.3 eq trifluoroacetic acid) as an orange oil. This material was dissolved in acetonitrile (3 mL) and used in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](O)=[N:8][C:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2].C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:26]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:26])=[N:8][C:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc(-c2ncccn2)nc1O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1cnc(-c2ncccn2)nc1Cl
Temperature: 25 °C
Yield: 82 %

Procedure:
A suspension of 1.62 g (6.5 mmol) 4-hydroxy-[2,2′]bipyrimidinyl-5-carboxylic acid ethyl ester in 16 ml POCl3 was heated at reflux for lh. The solution was cooled to RT and poured into 100 ml ice-water. The pH of the solution was adjusted to 8 with sat. NaHCO3-solution. The water phase was extracted three times with 80 ml CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 95:5) to give 1.43 g (82%) 4-chloro-[2,2′]bipyrimidinyl-5-carboxylic acid ethyl ester as a light brown solid, MS (EI): 264.1 (M+).
Reaction SMILES: [Li]CCCC.[Si:6]([O:13][CH2:14][CH2:15][O:16][CH2:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH3:23][O:24][C:25]([C:27]1[CH:28]2[N:43]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH:32]([CH2:33][C:34]=1OS(C(F)(F)F)(=O)=O)[CH2:31][N:30]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:29]2)=[O:26]>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[CH3:23][O:24][C:25]([C:27]1[CH:28]2[N:43]([C:44]([O:46][C:47]([CH3:50])([CH3:48])[CH3:49])=[O:45])[CH:32]([CH2:33][C:34]=1[C:20]1[S:19][C:18]([CH2:17][O:16][CH2:15][CH2:14][O:13][Si:6]([C:9]([CH3:12])([CH3:10])[CH3:11])([CH3:7])[CH3:8])=[N:22][CH:21]=1)[CH2:31][N:30]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:29]2)=[O:26]
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CC2CN(C(=O)OC(C)(C)C)CC1N2C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCOCc1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C1=C(c2cnc(COCCO[Si](C)(C)C(C)(C)C)s2)CC2CN(C(=O)OC(C)(C)C)CC1N2C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
BuLi (1.6 M in hexane, 5.70 mL, 9.05 mmol) was added dropwise to a cooled (−78° C.) solution of 2-[2-(tert-butyldimethylsilanyloxy)ethoxymethyl]thiazole (1.900 g, 6.786 mmol) in THF (15 mL). The reaction mixture was stirred at −78° C. for 1 h, and ZnCl2 (1M in THF, 11.3 mL, 11.3 mmol) was added dropwise at −78° C. The cooling bath was removed, and the reaction mixture was stirred for 1 h at rt. A sol. of compound Y (2.00 g, 3.77 mmol) in THF (5 mL) was added dropwise, followed by Pd(PPh3)4 (136 mg, 0.109 mmol). The reaction mixture was stirred at rt for 2 h, partitioned between EtOAc and aq. 1M NaOH, and the layers were separated. The aq. layer was extracted with EtOAc. The combined org. extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (heptane/EtOAc 7/3) yielded the title compound (1.60 g, 65%) as an orange oil. LC-MS: tR=1.19 min, ES+: 654.33.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][C:13]#[C:14][P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])=[CH:4][CH:3]=1>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[CH:8]=[C:9]1[CH2:10][CH2:11][CH2:12][C:13]1=[C:14]2[P:15](=[O:22])([O:16][CH2:17][CH3:18])[O:19][CH2:20][CH3:21]
Reactant: CCOP(=O)(C#CCCC/C=C/c1ccc(Cl)cc1)OCC
Solvent: Clc1ccccc1Cl
Product: CCOP(=O)(OCC)c1c2c(cc3ccc(Cl)cc13)CCC2
Temperature: 225 °C
Reaction time: 2.5 h

Procedure:
To a 0.5-2 mL microwave irradiation vial equipped with a stir bar was added enyne 5i (0.034 g, 0.10 mmol) in o-dichlorobenzene (1.7 mL). The reaction was irradiated with stirring at 225° C. for 150 min until complete by TLC. The reaction turned golden in color. The reaction was then transferred to a vial, concentrated under reduced pressure, and dried under vacuum to yield naphthalene 6i as an amber oil (0.034 g, quant.).
Reaction SMILES: [CH:1]1([C:9](=O)[CH2:10][CH3:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C([OH:15])C>[Pd]>[CH:1]1([CH2:9][C:10](=[O:15])[CH3:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(=O)C1CC=CCCCC1
Reactant: CCO
Agent: [Pd]
Product: CC(=O)CC1CCCCCCC1
Reaction time: 0.67 h
Yield: 52 %

Procedure:
A solution of 1-cyclooct-3-enylpropan-1-one (1.5 g, 9 mmol) in ethanol (20 ml) was treated with 10% palladium on charcoal (0.09 g) at room temperature and the resulting suspension was hydrogenated during 40 min. at 20 bars. After filtration through Celite® and concentration under vacuum, the crude product was purified by flash chromatography (hexane/Et2O 19:1) to give 0.78 g of 1-cyclooctylpropanone (52%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:16][N:17]4C(=O)C5=CC=CC=C5C4=O)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:6]=2[CH:34]=1.C(OCC)(=O)C.O.NN>C(O)C>[NH2:17][CH2:16][CH2:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:34][C:6]=3[C:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:8][CH2:9][C:10]2=[N:14][N:13]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: NN
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: NCCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 0.92 h

Procedure:
A stirred mixture of 8-chloro-6-phenyl-1-(2-phthalimidoethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, ethyl acetate solvate (37.6 g., 0.0675 mole) and absolute ethanol (340 ml.) is treated with hydrazine hydrate (7.43 g.) and warmed, under nitrogen, in an oil bath to 75° during 65 minutes, the bath is kept at this temperature for an additional 55 minutes. The mixture is then cooled in an ice bath, and the solid is collected by filtration and washed with absolute ethanol and methylene chloride. The combined filtrate is mixed with ice cold salt water and extracted with methylene chloride. The extract is washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel (1 kg.) with methanol and the resulting product is crystallized from methylene chloride diethyl ether to give 1-(2-aminoethyl)-8-chloro-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine in 2 crops: 5.29 g. of melting point 198°-200° C. dec., and 2.37 g., of melting point 194°-196.5° C. dec. The analytical sample is crystallized from methanol-ethyl acetate and has a melting point of 205°-207° C.