Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([OH:14])=O.[CH2:15]([O:17][C:18](=[O:34])[CH2:19][CH:20]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([NH2:33])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH2:21][CH2:22][CH3:23])[CH3:16].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:15]([O:17][C:18](=[O:34])[CH2:19][CH:20]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([NH:33][C:12](=[O:14])[CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[CH2:6][CH2:7][CH2:8][NH:9][C:10]=4[N:1]=3)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH2:21][CH2:22][CH3:23])[CH3:16]
Reactant: O=C(O)Cc1ccc2c(n1)NCCC2
Reactant: CCCC(CC(=O)OCC)n1ccc2cc(N)ccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC(CC(=O)OCC)n1ccc2cc(NC(=O)Cc3ccc4c(n3)NCCC4)ccc21
Yield: 68.6 %

Procedure:
A solution of (5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-acetic acid (0.2 g, 0.65 mmol), 3-(5-amino-indol-1-yl)-hexanoic acid ethyl ester (0.19 g, 0.71 mmol), BOP (0.35 g, 0.78 mmol), and diisopropylethylamine (0.45 mL, 2.6 mmol) in DMF (2.5 mL) was stirred for 16 h. Solvents were evaporated. The resulting residue was partitioned between H2O and EtOAc. The aqueous layer was separated and extracted once more with EtOAc. The extracts were combined, washed with H2O, brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel, eluting with EtOAc/DCM (15, 30, 50, and 80%) to give the title compound (0.20 g, 67% yield) as a brown oil. Mass spectrum (LCMS, ESI) calculated for C26H33N4O3 449.3 (M+H); found 449.3.
Reaction SMILES: [OH:1][CH:2]1[CH:6](N)[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:15]([NH:25][C@H:26]([C:31](O)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CCOC(C)=O>[CH3:12][C:11]([O:10][C:8]([N:4]1[CH2:5][CH:6]([C:31](=[O:32])[C@H:26]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH:25][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH:2]([OH:1])[CH2:3]1)=[O:9])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC(N)C(O)C1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)C1CN(C(=O)OC(C)(C)C)CC1O
Yield: 65.6 %

Procedure:
To a solution of 3-hydroxy-4-amino-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester (202 mg, 1.14 mmol) in CH2CI2 (5 mL) was added CBZ-leucine (302.9 mg, 1.14 mmol), HOBT (154 mg, 1.14 mmol) and EDC (262.2 mg, 1.37 mmol). The reaction was allowed to stir until complete by TLC analysis whereupon it was diluted with EtOAc and washed sequentially with pH 4 buffer, sat. K2CO3, water and brine. The organic layer was dried (MgSO4), filtered and concentrated. Column chromatography of the residue (3:1 EtOAc:hexanes) gave 325 mg of the title compound: MS (ES+) 450.3 (MH+), 472.2 (M+Na).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([O:7]CC1C=CC=CC=1)=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>CN(C=O)C.CCOC(C)=O.[Pd]>[C:29]([O:28][C:26](=[O:27])[CH2:25][O:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(OCc1ccccc1)c1cccc(O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 7-2 (3.6 g, 16 mmol) in DMF (50 mL) was added Cs2CO3 (7.8 g, 238 mmol). After 15 min., tert-butyl bromoacetate (3.2 mL, 35 mmol) was added and the reaction mixture stirred for 20 hrs at ambient temperature. The reaction mixture was diluted with EtOAc and then washed with H2O, and brine, dried (MgSO4), and concentrated to give a yellow oil. The crude yellow oil (5.4 g, 15.8 mmol), 10% Pd/C (500 mg), and EtOAc (100 mL) was stirred under a hydrogen atmosphere (1 atm) for 20 hr. The reaction mixture was then filtered through a celite pad and the filtrate concentrated to give 7-3 as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:5])C.[OH-].[Li+].C(Cl)Cl>CO.O>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[O:9][CH:8]=[N:7][C:6]=2[C:4]([OH:5])=[O:3])=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ncoc1-c1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=C(O)c1ncoc1-c1ccc(Br)cc1
Temperature: 60 °C

Procedure:
5-(4-Bromo-phenyl)-oxazole-4-carboxylic acid ethyl ester (1.0 g, 3.4 mmol) was dissolved in MeOH:H2O (5:1, 60 mL) and then lithium hydroxide (1.0 g, 41.8 mmol) was added. The reaction was heated to 60° C. for 10 minutes then allowed to cool. The reaction was submitted to acidic aqueous/CH2Cl2 workup then concentrated to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[CH:16]=3)[C:11](=[O:24])[C:10]([C:25]([NH2:27])=[O:26])=[CH:9]2)=[CH:4][CH:3]=1.[CH2:28]=O.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>C(O)C>[CH2:30]([N:32]([CH2:28][NH:27][C:25]([C:10]1[C:11](=[O:24])[C:12]2[C:17](=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:9]=1)=[O:26])[CH2:33][CH3:34])[CH3:31]
Reactant: NC(=O)c1cn(-c2ccc(F)cc2)c2cc(-c3ccncc3)ccc2c1=O
Reactant: CCNCC
Reactant: C=O
Solvent: CCO
Product: CCN(CC)CNC(=O)c1cn(-c2ccc(F)cc2)c2cc(-c3ccncc3)ccc2c1=O

Procedure:
A mixture of 2.2 g 1-(4-fluorophenyl)-1,4-di -hydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxamide (Example 1h) and molar excess amounts of formaldehyde and diethylamine in 100 ml ethanol was heated at reflux for two days. The ethanol was removed and the residual product chromatographed on silica gel. The column was eluted with 10% isopropyl alcohol in chloroform; starting material was eluted first followed by fractions containing the desired N-diethylaminomethyl compound. The latter was recrystallized from ethyl acetate to give 0.9 g N-(diethylaminomethyl)-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxamide, m.p. 193195° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Br[CH2:14][CH3:15]>O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:14][CH3:15])[C:11]#[N:12])=[CH:6][CH:5]=1
Reactant: CCBr
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 0.42 g (10.5 mmol) NaH (60% dispersion in mineral oil) were added at ambient temperature 1.67 g (11 mmol) 4-chlorophenyl-acetonitrile in 10 ml anhydrous tetrahydrofuran. The reaction mixture was stirred at ambient temperature for 2 hours and then cooled to −20° C. 0.78 ml (10.5 mmol) Bromoethane was added drop-wise to the reaction mixture over 30 minutes. The reaction was warmed to ambient temperature while stirring over 2 hours. The reaction mixture was quenched by addition of 20 ml of saturated ammonium chloride solution. Dichloromethane was added, the organic phase was separated and the aqueous phase washed with dichloromethane. The combined organic phase was dried over MgSO4 and evaporated to afford rac-2-(4-chloro-phenyl)butyronitrile as a brown oil that did not require further purification. NMR (CDCl3, ppm): 0.80 (3H, t), 1.82 (2H, dq), 3.64 (1H, t), 7.30-7.15 (4H, m).
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.CS(C)=O.[Si:11]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[Si:11]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH:23]([OH:24])[CH:1]=[CH2:2])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCOCCO
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C=CC(O)COCCO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of oxalyl chloride (8.38 mL) in dichloromethane (470 mL) was cooled to −78° C. in a nitrogen atmosphere. A solution of dimethyl sulfoxide (8.01 mL) in dichloromethane (10 mL) was added dropwise to the reaction solution at the same temperature. The reaction solution was stirred at the same temperature for 10 minutes. A solution of 2-[2-(tert-butyldimethylsilanyloxy)ethoxy]ethanol (25.9 g) in dichloromethane (20 mL) was added dropwise to the reaction solution at the same temperature. The reaction solution was stirred at the same temperature for 30 minutes. Triethylamine (52.1 mL) was added to the reaction solution at the same temperature. The reaction solution was stirred for one hour while gradually returning to room temperature. Aqueous ammonium chloride was added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was filtered through a silica pad and the filtrate was concentrated. Tetrahydrofuran (500 mL) was added to the residue. The reaction solution was cooled to −78° C. in a nitrogen atmosphere. Vinylmagnesium chloride (148 mL, 1.38 M solution in tetrahydrofuran) was added dropwise to the reaction solution at the same temperature. The reaction solution was heated to room temperature with stirring over six hours. Aqueous ammonium chloride and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (10.03 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>[Li+].C[Si]([N-][Si](C)(C)C)(C)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][CH:5]1[CH2:4][C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[Br:1])[C:6]1=[O:11])[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCc2c(Br)cccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCOC(=O)CC1Cc2c(Br)cccc2C1=O
Temperature: 0 °C
Yield: 87.5 %

Procedure:
To a solution of 4-bromoindanone (15.8 g, 75 mmol) at −78° C. was added LiHMDS (1 M in THF, 90 mL). The slight brown solution was allowed to warm up to 0° C., and was cooled again to −75° C. and ethyl 2-bromoacetate (9.1 mL, 82 mmol) was added dropwise. The mixture was allowed to warm up over night (−75° C. to −20° C. over 12 h). The mixture was quenched with sat. ammonium chloride and was extracted with ethyl acetate. Flash chromatography give 19.5 g of the title compound in a mixture with the starting indanone ethyl 2-[4-bromo-2-(2-ethoxy-2-oxo-ethyl)-1-oxo-indan-2-yl]acetate and which was used without further purification for the next step (purity, 60% of the desired product). LC-MS (Method A) RT 1.11 min., 297/299 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH:8](O)[CH2:7]2.[CH2:13]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH:8]([N:16]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:14][CH3:15])[CH2:7]2
Reactant: OC1COc2c(Br)cccc2C1
Reactant: CCCNCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCN(CCC)C1COc2c(Br)cccc2C1
Reaction time: 8 h

Procedure:
8-Bromo-3-chromanol (80% according to GC, 0.8×0.69 g, 0.8×3.0=2.4 mmol) was dissolved in dry benzene and di-n-propylamine (2 ml) and p-toluenesulfonic acid (60 mg) was added. The reaction mixture was refluxed under N2 and water separation in a Dean-Stark apparatus. The solvents were removed under reduced pressure and the residue was dissolved in MeOH (50 ml) and NaBH3CN (2.0 g) was added and the mixture was stirred overnight. Water (50 ml) and 15% NaOH (5 ml) was added and the product was extracted to CH2Cl2. The organic layer was washed with water, dried (Na2SO4), filtered and the solvents were removed under reduced pressure, leaving 700 mg of the raw product, which was chromatographed (SiO2, 100 g) using petroleum ether:ether (9:1) as the eluant. The fractions containing pure product were pooled and the solvent was evaporated. The residual oil was converted into the hydrochloride with HCl-saturated EtOH. Crystals (248 mg) melting at 135° C. were obtained from EtOAc/ether. GC/MS showed M+ /M+2 at m/e=311.05(7.7%)/313.05(8.7%) and the base peak pair at m/e=281.95(98%)/283.95(100%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([I:11])=[C:7]([CH:10]=1)[CH2:8]Br.[C-:14]#[N:15].[Na+]>CCO.O>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([I:11])=[C:7]([CH2:8][C:14]#[N:15])[CH:10]=1
Reactant: [C-]#N
Reactant: FC(F)(F)c1ccc(I)c(CBr)c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1cc(C(F)(F)F)ccc1I
Temperature: 25 °C

Procedure:
A solution of 5-trifluoromethyl-2-iodobenzyl bromide (55 g, 0.15 mol) in EtOH (200 mL) is stirred at room temperature and a solution of sodium cyanide (16 g, 0.33 mol) in water (60 mL) is added. The reaction mixture is heated to reflux temperature for 3 hours and then cooled to room temperature. Most of the ethanol is removed by rotary evaporator and the residue partitioned between EtOAc (500 mL) and water (200 mL). The organic layer is washed with brine (250 mL), dried (MgSO4) and the solvent is removed by rotary evaporator. The residue is purified using flash chromatography (1:9 EtOAc/hexanes) to give 5-trifluoromethyl-2-iodophenylacetonitrile as a solid.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)(N1C=CN=C1)=O.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:14]1.[CH3:27][C:28]1(C)[C:32](=[N:33]O)[CH2:31][C:30]2(CCNC[CH2:35]2)[O:29]1.ClCCl>C1COCC1>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][C:24]([O:26]/[N:33]=[C:32]2/[CH:28]([CH3:27])[O:29][C:30]3([CH2:35][CH2:9][N:8]([CH3:1])[CH2:12][CH2:11]3)[CH2:31]/2)=[O:25])=[CH:14]1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(C)OC2(CCNCC2)CC1=NO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1OC2(CCN(C)CC2)C/C1=N\OC(=O)CCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Carbonyldiimidazole (CDI) (0.19 g, 1.2 mmol) was added to a solution of 3-indole propionic acid (0.22 g, 1.2 mmol) in dry THF (10 ml) under an argon atmosphere. The reaction mixture was stirred for 0.5 h at room temperature, then dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one oxime (0.23 g, 1.2 mmol, prepared according to the procedure of Tsukamoto et. al. Chem. Pharma. Bull. 1995, 43, 842-852) was added. The reaction mixture was stirred for 4 h at room temperature and then for 8 h at 45° C. The reaction mixture was cooled to room temperature, dichloromethane (80 ml) was added and the mixture was washed with water (10 ml). The two phases were separated and the aqueous phase was extracted with dichloromethane (30 ml). The organic phases were combined, dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography in a Combi-Flash Companion system (Isco, Inc) (HP 12-gold silica column, CH2Cl2/MeOH/NH4OH 90/10/1) followed by further flash chromatography in a Combi-Flash Companion system (Isco, Inc) (HP 12-gold silica column, CH2Cl2/MeOH/NH4OH 120/10/1). The residue was triturated in ether to give AF733 (104 mg), obtained as a white solid. 1H NMR (CDCl3, 300 MHz) δ 8.17 (br s, 1H, NH-indole), 7.60 (d, J=7.73 Hz, 1H, CHC arom), 7.35 (d, J=7.98 Hz, 1H, CHC arom), 7.19 (app t, J=7.76 Hz, 1H, CHCH arom), 7.12 (app t, J=7.43 Hz, 1H, CHCH arom), 7.04 (d, J=2.11 Hz, 1H, CHNH arom), 5.56 (q, J=6.3 Hz, 1H, CHCH3), 3.18 (t, J=7.37 Hz, 2H, CH2), 2.83 (t, J=7.41 Hz, 2H, COCH2), 2.40 (ABq, J=18.6 Hz, 2H, CH2), 2.5-2.3 (m, 4H), 2.28 (s, 3H, NCH3), 1.74 (2m, 3H), 1.5 (m, 1H), 1.43 (d, J=6.36 Hz, 3H, CH3—CH) ppm; 13C NMR (CDCl3, 300 MHz) δ 173.4 (C), 171.0 (C), 136.5 (C), 127.3 (C), 122.2 (CH), 122.1 (CH), 119.5 (CH), 118.8 (CH), 114.5 (C), 111.4 (CH), 78.7 (C), 72.5 (CH), 52.5 (CH2), 52.2 (CH2), 46.1 (CH3), 40.0 (CH2), 37.4 (CH2), 34.4 (CH2), 33.7 (CH2), 20.9 (CH2), 19.5 (CH3) ppm.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.Cl[C:9]1[N:10]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([C:24]1[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=1)[N:12]=2.[CH:36]([N:39](C(C)C)CC)(C)C>C(Cl)Cl.CO>[CH2:4]1[C:5]2([CH2:6][N:2]([C:9]3[N:10]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:11]4[C:16]([N:17]=3)=[C:15]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[N:14]=[C:13]([C:24]3[CH:29]=[N:28][C:27]([NH2:30])=[N:26][CH:25]=3)[N:12]=4)[CH2:1][CH2:36][NH:39]2)[CH2:3]1
Reactant: CN1CCCC1=O
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC(F)(F)F)c3n2)cn1
Solvent: CO
Solvent: ClCCl
Product: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCNC5(CC5)C4)n(CC(F)(F)F)c3n2)cn1
Temperature: 100 °C
Reaction time: 96 h
Yield: 26 %

Procedure:
Potassium carbonate (1.19 g, 8.58 mmol) was added to a methanol solution (10 ml) of 4-(trifluoroacetyl)-4,7-diazaspiro[2.5]octane hydrochloride (1.0 g, 4.09 mmol) at room temperature and the resulting mixture was stirred at 50° C. for 16 hours. The resulting mixture was left standing to cool, then potassium carbonate was removed by filtration, and the filtrate was concentrated to give crude 4,7-diazaspiro[2.5]octane. This compound was added to an N-methyl-2-pyrrolidone suspension of 5-[8-chloro-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (277.4 mg, 0.67 mmol) and dissolved at 120° C. followed by the addition of diisopropylethylamine (1.16 ml, 6.69 mmol) and the resulting mixture was stirred at 100° C. for 4 days. The resulting mixture was left standing to cool, then poured into methylene chloride-methanol (10:1), and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel column chromatography (methylene chloride:methanol=24:1 to 12:1) to give the title compound (83.3 mg, 26%) as a brown amorphous solid.
Reaction SMILES: [CH2:1]([O:3]C1C=CC(S(Cl)(=O)=O)=CC=1C1NC(=O)C2=C(C)N=C(C)N2N=1)[CH3:2].ON1CCNCC1.[CH2:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([N:45]2[CH2:50][CH2:49][N:48](O)[CH2:47][CH:46]2CC)(=[O:44])=[O:43])=[CH:38][C:37]=1[C:54]1[NH:59][C:58](=[O:60])[C:57]2=[C:61]([CH3:65])[N:62]=[C:63]([CH3:64])[N:56]2[N:55]=1)[CH3:34]>>[CH2:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([N:45]2[CH2:50][CH2:49][N:48]([CH2:2][CH2:1][OH:3])[CH2:47][CH2:46]2)(=[O:43])=[O:44])=[CH:38][C:37]=1[C:54]1[NH:59][C:58](=[O:60])[C:57]2=[C:61]([CH3:65])[N:62]=[C:63]([CH3:64])[N:56]2[N:55]=1)[CH3:34]
Reactant: CCOc1ccc(S(=O)(=O)N2CCN(O)CC2CC)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1
Agent: ON1CCNCC1
Product: CCOc1ccc(S(=O)(=O)N2CCN(CCO)CC2)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1

Procedure:
By the same method, starting with 100 mg (0.261 mmol) of 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 100 mg (0.784 mmol) of 4-hydroxypiperazine, 45 mg (36.1% of theory) of 2-[2-ethoxy-5-(4-hydroxy-ethylpiperazine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f]-[1,2,4]triazin-4-one are obtained.
Reaction SMILES: [B-].[Na+].O.[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([C:30]4[N:34]([CH3:35])[CH:33]=[N:32][CH:31]=4)([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)[NH2:22])[CH:19]=3)[N:14]3[N:36]=[N:37][N:38]=[C:13]3[N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(Cl)Cl>CO>[Cl:4][C:5]1[CH:6]=[C:7]([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([C:30]4[N:34]([CH3:35])[CH:33]=[N:32][CH:31]=4)([C:23]4[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=4)[NH2:22])[CH:19]=3)[N:14]3[N:36]=[N:37][N:38]=[C:13]3[NH:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1ccc(C(N)(c2ccc3c(c2)c(-c2cccc(Cl)c2)nc2nnnn23)c2cncn2C)cc1
Agent: [B-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(N)(c2ccc3c(c2)C(c2cccc(Cl)c2)Nc2nnnn2-3)c2cncn2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
Sodium hydroborate (0.0005 mol) was added portionwise at room temperature to a mixture of intermediate 27 (0.0005 mol) in methanol (2.5 ml). The mixture was stirred at room temperature for 2 hours and poured out into ice water. DCM was added. The mixture was extracted with DCM. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over kromasil® (5 μm) (eluent: DCM/MeOH/Et3N 97/3/0.3). The pure fractions were collected and the solvent was evaporated. The residue (0.1 g, 40%) was taken up in diethyl ether and dried in a vacuo, yielding 0.07 g (28%) of 5-(3-chlorophenyl)-4,5-dihydro-α-(1-methyl-1H-imidazol-5-yl)-α-(4-methylphenyl)-tetrazolo[1,5-a]quinazoline-7-methanamine (intermediate 28), mp. 140° C.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[I-:19].[Na+].[CH3:21]C(C)=O>>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][CH:6]([CH2:21][I:19])[CH2:7][CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)=O
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(CI)CC1

Procedure:
A mixture of 1-(t-butoxycarbonyl)piperidin-4-yl methanesulfonate (13.58 g, 46.4 mmol) and sodium iodide (34.68 g, 232 mmol) in acetone (80 mL) was heated to reflux for 3 h. The mixture was partitioned between ether (350 mL) and water (350 mL). The organic layer was washed with saturated aq. brine (250 mL), and the aqueous layers were extracted in succession with ether (250 mL). The combined organic layers were dried (sodium sulfate), decanted, and evaporated to give the title compound (14.8 g) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:9][C:10]1[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Li])CCC.[BH:22]([OH:24])[OH:23]>C1COCC1.CCCCCC.C(OCC)C.[Cl-].[Cl-].[Zn+2]>[CH2:1]([O:9][C:10]1[N:11]=[N:12][C:13]([B:22]([OH:24])[OH:23])=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(Cl)nn1
Reactant: OBO
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(B(O)O)nn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
17.1 g (70.6 mmol) of 3-octyloxy-6-chloropyridazine are dissolved in 100 ml of absolute THF and cooled to -78° C. under a protective gas. 47.1 ml (75.2 mmol) of 1.6 molar n-butyllithium solution in hexane are then added dropwise over the course of 30 minutes. The mixture is stirred at -78° C. for a further 30 minutes. 216 ml (215.7 mmol) of 1.0 molar ZnCl2 solution in diethyl ether are subsequently slowly added dropwise, during which the temperature must not exceed -60° C. When the addition is complete, the mixture is stirred for a further 30 minutes. The crude boronic acid is employed directly, without isolation from the solution, for the subsequent couplings.