Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 72.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.27 g, 0.438 mmol) prepared in Example 48a, triethylsilane (0.168 mL, 1.05 mmol), trifluoroacetic acid (3.4 mL) and dichloromethane (3.4 mL), to yield the title compound (0.148 g, 72%) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1C(OC(C)(C)C)=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.Cl>O1CCOCC1>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][N:2]([CH3:1])[CH2:18][C@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)=[CH:9][CH:8]=2)=[CH:16][CH:15]=1
Reactant: CN(Cc1ccc(Oc2ccc(Br)cc2)cc1)C[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CN(Cc1ccc(Oc2ccc(Br)cc2)cc1)C[C@H]1CCCN1
Yield: 128.8 %

Procedure:
A solution of 1,1-dimethylethyl (R)-2-[[methyl[[4-(4-bromophenoxy)phenyl]methyl]amino]methyl]-1-pyrrolidinecarboxylate (670 mg, 1.8 mmol) in a solution of 4 N hydrochloric acid in dioxane (6 mL) was stirred overnight. Solvent was removed under reduced pressure and 870 mg of (R)—N—[[4-(4-bromophenoxy)phenyl]methyl]-N-methyl-2-pyrrolidinemethanamine was isolated as the hydrochloride salt.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]([CH2:28][C:29]([O:31]C)=[O:30])[CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2.O[Li].O>CO.O>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([N:14]1[CH2:15][CH2:16][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]([CH2:28][C:29]([OH:31])=[O:30])[CH2:20]3)[CH2:18][CH2:19]1)=[O:13])[CH2:8]2
Reactant: COC(=O)CC1CC2(CCN(C(=O)OC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)CC1CC2(CCN(C(=O)OC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
2-adamantyl-3-(2-methoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (26 mg, 0.06 mmol) was dissolved in MeOH (1 mL) in an ice-water bath. A solution of LiOH.H2O (4.99 mg, 0.119 mmol) in water (0.2 mL) was added dropwise and the mixture was stirred for 8 h at rt. LC-MS showed that the starting material was consumed completely. The mixture was evaporated to give a residue, which was purified by preparative HPLC to afford 2-(1′-((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid (12.2 mg, 48%). 1H NMR (400 MHz, CD3OD): δ=0.91 (m, 2H), 1.32 (m, 3H); 1.53-1.71 (m, 6H), 1.75-1.93 (m, 8H), 1.93-2.18 (m, 4H), 2.24 (m, 1H), 2.63 (m, 1H), 2.77 (m, 1H), 2.96-3.24 (br, 2H), 3.62 (m, 1H), 4.10-4.28 (br, 2H), 4.72 (s, 1H), 7.15 (m, 3H), 7.24 (m, 1H).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:12][S:13]([C:6]1[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=1[O:8][CH3:9])[C:1]([OH:11])=[O:10])(=[O:15])=[O:14]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: O=S(=O)(O)Cl
Product: COc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of chlorosulfonic acid (90 mL) at room temperature is treated with p-anisic acid (40 g), portionwise, during 30 minutes. When the addition is complete, the mixture is stirred at 90° C. for 75 minutes, then it is cooled and poured onto ice. The white precipitate is collected and dissolved in ethyl acetate (300 mL). The organic extract is washed with brine (2×250 mL), dried over magnesium sulfate, and concentrated, to give 3-chlorosulfonyl-4-methoxybenzoic acid (34 g), in the form of a white solid m.p. 168°-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:8]([CH2:19][NH2:20])=[CH:7]2.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:8]([CH2:19][NH:20][C:22]1[N:30]=[CH:29][N:28]=[C:27]3[C:23]=1[N:24]=[CH:25][NH:26]3)=[CH:7]2
Reactant: NCc1cc2cccc(Cl)c2nc1-c1cccc(F)c1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Fc1cccc(-c2nc3c(Cl)cccc3cc2CNc2ncnc3[nH]cnc23)c1

Procedure:
Prepared according to Procedure H using (8-chloro-2-(3-fluorophenyl)quinolin-3-yl)methanamine (0.030 g, 0.11 mmol), 6-Chloropurine (0.019 g, 0.13 mmol, 1.2 eq) and DIEA in n-butanol (3 mL). N-((8-chloro-2-(3-fluorophenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=74 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.41 (s, 1 H), 8.13 (s, 1 H), 7.88-8.02 (m, 4 H), 7.59 (dd, J=4.40, 2.20 Hz, 4 H), 4.80-4.98 (m, 2 H), Mass Spectrum (ESI) m/e=405 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:2]1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[S:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[CH:24][CH:23]=1.C(N(CC)CC)C>ClCCl>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[S:26][C:25]([S:27]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:3][CH2:2]2)(=[O:29])=[O:28])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC1CCN(S(=O)(=O)c2ccc(-c3ccccn3)s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
tert-Butyl piperidin-4-ylmethylcarbamate (0.100 g) in dichloromethane (2.3 mL) was treated with 5-(pyridin-2-yl)thiophene-2-sulfonyl chloride (0.133 g), followed by triethylamine (0.325 mL) at room temperature. After stirring the mixture at room temperature overnight, it was washed with 1N hydrochloric acid, the organic layer was separated and filtered. Evaporation of the solvent and purification by column chromatography on silica gel (1-4% methanol in dichloromethane) provide the title compound (0.088 g) having the following physical data.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCNC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 75.3 %

Procedure:
A mixture of 2-tert-butoxycarbonylaminoethanol (32.7 g, 203 mmol), triethylamine (34 ml), p-toluenesulfonyl chloride (38.7 g, 203 mmol), 4-dimethylaminopyridine (0.10 g) and dichloromethane (500 ml) was stirred at 0° C. for 4 hours. The reaction mixture was washed successively with water, 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent:ethyl acetate/n-hexane= 1/5) to obtain 48.2 g of 2-tert-butoxycarbonylaminoethyl 4-toluenesulfonate.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])=[O:2].OS(O)(=O)=O.[CH2:18](Cl)Cl.O>CO>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([CH:11]=1)[C:8]([O:10][CH3:18])=[O:9])=[O:2]
Reactant: ClCCl
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(C=O)ccc1O
Temperature: 50 °C

Procedure:
To a solution of 5-formyl-2-hydroxybenzoic acid (3 g, 18.06 mmol) in methanol (10 ml) was added H2SO4 (0.5 ml, 9.38 mmol). The solution was heated at 50° C. for 18 hours. The solution was cooled, and DCM (30 ml) and water (20 ml) were added. The organic layer was separated, washed with NaHCO3 (10 ml), dried (MgSO4) and the solvent removed in vacuo to yield the title compound as a yellow solid. 3.1 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([CH3:11])[CH3:10].C(N(CC)CC)C>O1CCOCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:15]2[CH2:16][CH2:17][N:12]([CH:9]([CH3:11])[CH3:10])[CH2:13][CH2:14]2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)N1CCN(c2cncc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 2,6-dichloropyrazine (250.0 mg, 1.678 mmol) in 1,4-dioxane (2 mL) was added 1-isopropylpiperazine (0.29 mL, 2.014 mmol) and triethylamine (0.70 mL, 5.034 mmol). The reaction mixture was stirred at room temperature for 1 day, filtered through Celite (1,4-dioxane eluent) then concentrated. Purification by flash column chromatography on silica gel using 100:5:1 EtOAc/MeOH/NH4OH (0 to 100%) in EtOAc provided the product. LCMS-ESI+ calc'd for C11H18ClN4 (M+H+): 241.1; Found: 241.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@@H:11]2[CH2:13][C@H:12]2[CH2:14][NH:15]C(=O)OC(C)(C)C)=[N:3]1.[ClH:23].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:23].[ClH:23].[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@@H:11]2[CH2:13][C@H:12]2[CH2:14][NH2:15])=[N:3]1
Reactant: Cn1cc2c([C@@H]3C[C@H]3CNC(=O)OC(C)(C)C)cccc2n1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cn1cc2c([C@@H]3C[C@H]3CN)cccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of tert-butyl {[(1R,2R)-2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}carbamate (2.68 g, 8.89 mmol) in ethyl acetate (50 mL) was added 4 M hydrochloric acid/ethyl acetate (50 mL) solution, and the mixture was stirred at room temperature for 2 hr. The solvent was concentrated under reduced pressure, and the obtained crystals were washed with ethyl acetate to give the title compound (2.38 g, yield 98%).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:13]3[N:14]=[CH:15][CH:16]=[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:12]3=[N:11][C:10]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][CH:4]=1)#[N:2].[NH4+].[Cl-].[N-:31]=[N+:32]=[N-:33].[Na+]>>[NH:31]1[C:1]([C:3]2[N:8]=[CH:7][C:6]([C:9]3[N:13]4[N:14]=[CH:15][CH:16]=[C:17]([N:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)[C:12]4=[N:11][C:10]=3[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][CH:4]=2)=[N:2][N:33]=[N:32]1
Reactant: CCOC(=O)c1nc2c(N3CCOCC3)ccnn2c1-c1ccc(C#N)nc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CCOC(=O)c1nc2c(N3CCOCC3)ccnn2c1-c1ccc(-c2nnn[nH]2)nc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
Compound 32a (378 mg, 1.00 mmol), NH4Cl (80.2 mg, 1.50 mmol), and NaN3 (97.5 mg, 1.50 mmol) were placed in an 8 mL vial equipped with a stir bar and then the vial was evacuated and backflushed with argon. Dry DMF (4 mL) was added and then the reaction was stirred at 110° C. for 1 h. The reaction was cooled to rt and poured into water (25 mL). The pH of the mixture was adjusted with 2 M HCl to pH 2 and then the precipitate was isolated by filtration. The solid was dried under reduced pressure to afford compound 32b. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (s, 1H), 8.29-8.40 (m, 2H), 8.23 (d, J=5.6 Hz, 1H), 6.50 (d, J=5.6 Hz, 1H), 4.23 (q, J=6.8 Hz, 2H), 4.01-4.11 (m, 4H), 3.77-3.86 (m, 4H), 1.16 (t, J=7.0 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C19H19N9O3: 422.2 (M+H). Found: 422.2.
Reaction SMILES: Br[CH:2]([CH2:11][CH3:12])[C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]([NH2:21])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][C:3]1[N:21]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:20][C:2]=1[CH2:11][CH3:12])[CH3:9]
Reactant: CCOC(=O)CC(=O)C(Br)CC
Reactant: NC(=O)c1ccccc1
Product: CCOC(=O)Cc1nc(-c2ccccc2)oc1CC
Yield: 19.6 %

Procedure:
The title compound was prepared (as described above for the preparation of example 1) from ethyl 4-bromo-3-oxo-hexanoate (3.32 g, 14 mmol) and 6.79 g (56 mmol) of benzamide to give 710 mg of Intermediate 1B: TLC Rf=0.69 (2/1 hexanes/EtOAc); 1H NMR (CDCl3, 300 MHz) δ7.98 (m, 2H), 7.41 (m, 3H), 4.18 (q, 2H, J=6.9), 3.57 (s, 2H), 2.72 (q, 2H, J=7.5), 1.29-1.24 low resolution MS (ES+)m/e 260.1 (MH+).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH3:13])[N:3]=1.C([Mg]Cl)(C)C.[CH2:19]([Sn:23]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])Cl)[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH3:13][N:4]1[C:5]2[C:10](=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=2)[C:2]([Sn:23]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH3:22])=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1nc(I)c2cc(C#N)ccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(C#N)cc12
Temperature: -16 °C
Reaction time: 0.5 h

Procedure:
In a round-bottomed flask, 3-iodo-1-methyl-1H-indazole-5-carbonitrile (383 mg, 1.35 mmol) was partially dissolved in THF (10 ml). The light yellow suspension was cooled to −16° C. (NaCl/ice bath) and isopropylmagnesium chloride (2.0 M in THF, 0.82 ml, 1.64 mmol) was added dropwise. The reaction mixture was stirred at −16° C. for 30 min then tributylchlorostannane (0.43 ml, 1.59 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 h then quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to provide 1-methyl-3-tributylstannanyl-1H-indazole-5-carbonitrile as a brown oil which was used without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[C:10]2[C:22]3[N:21]4[CH:23]=[CH:24][N:25]=[C:20]4[C:19](=[O:26])[NH:18][C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O>[Pd].CO>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[C:22]3[N:21]4[CH:23]=[CH:24][N:25]=[C:20]4[C:19](=[O:26])[NH:18][C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c2c3ccccc3c(=CCCc3ccccc3)c2n2ccnc12
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: O=c1[nH]c2c(n3ccnc13)C(CCCc1ccccc1)c1ccccc1-2
Yield: 28 %

Procedure:
The procedure is performed as in Example 13, but starting with 3.9 g of 10-(phenylpropylidene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 180 ml of dimethylformamide, 20 ml of methanol and 0.5 g of 10% palladium on charcoal. The crude product (3.8 g) is purified by chromatography on a column of silica (380 g partially deactivated with 10 ml of water), eluting with a mixture of dichloromethane and methanol (90/10 by volume). After trituration in 10 ml of dichloromethane, filtration and drying at 100° C., 1.1 g of 10-(phenylpropyl)-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one are obtained, in the form of a beige solid melting at 232° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[CH:8]=[C:9]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[CH:10]=1)=[O:4].[H-].[Na+].[CH2:26](I)[CH3:27]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[CH:8]=[C:9]([N:11]([CH2:26][CH3:27])[C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[CH:10]=1)=[O:4]
Reactant: CCI
Reactant: COC(=O)c1cc(NC(=O)C(C)C)cc(-c2ccc(C)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)C(C)C)c1cc(C(=O)OC)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
5-Isobutyrylamino-4′-methyl-biphenyl-3-carboxylic acid methyl ester (0.786 g, 2.32 mmol) and NaH (6.2 g, 2.55 mmol) were added to DMF (20 mL), and the mixture was stirred for 30 minutes at room temperature, then cooled to 0° C. Ethyl iodide (1.181 g, 11.6 mmol) was added, and the reaction mixture was stirred for five days at room temperature. The reaction was quenched by addition of saturated aqueous NH4Cl and water, and the mixture was extracted with diethyl ether. The combined organic layers were separated, washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (30% ethyl acetate in hexanes) to give 0.461 g of 5-(ethyl-isobutyryl-amino)-4′-methyl-biphenyl-3-carboxylic acid methyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[NH:12][C:13](=[O:15])[CH2:14][N:6]1[CH2:5]2.Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:15]=[C:13]1[CH2:14][N:6]2[C:7](=[N:8][C:9]3[C:4]([CH2:5]2)=[CH:3][C:2]([O:1][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:11][CH:10]=3)[NH:12]1
Reactant: CCOC(=O)CCCBr
Reactant: O=C1CN2Cc3cc(O)ccc3N=C2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc2c(c1)CN1CC(=O)NC1=N2
Temperature: 100 °C

Procedure:
To a solution of 7-hydroxy-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one (2.6 g) made as per U.S. Pat. No. 3,932,407 and ethyl 4-bromobutyrate (1.72 ml) in 100 ml dimethylformamide was added 1.86 g potassium carbonate. The reaction mixture was sealed under a blanket of nitrogen and heated to 100° C. for 4 hours. The reaction mixture was cooled, poured into 100 ml of water, and the resulting precipitate collected by filtration. Recrystallization from dimethylformamide-water gave ethyl 4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyrate, m.p. 243°-244° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:14][CH2:15][C@H:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].CCN(CC)CC.[CH3:28][C:29](OC(C)=O)=[O:30]>C(Cl)Cl>[C:29]([N:17]1[CH2:18][CH2:19][CH2:20][C@@H:16]1[CH2:15][O:14][C:6]1[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:30])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cc(OC[C@H]2CCCN2)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC[C@@H]1COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(2R)-2-(((3-nitro-5-(trifluoromethyl)phenyl)oxy)methyl)pyrrolidine (3.46 g, 11.9 mmols, 1 eq) was dissolved in 100 mL of CH2Cl2. Et3N (5 mL, 35.7 mmols, 3 eq) was added followed by Ac2O (1.2 mL, 13.1 mmols, 1.1 eq). The reaction was stirred at RT for 1.5 h. The solvent was removed in vacuo and the residue dissolved in EtOAc. The solution was washed once each with saturated NH4Cl, 1 N HCl, and twice with brine. The organic layer was dried over Na2SO4 filtered and concentrated in vacuo. The crude material was purified on a Biotage chromatography system eluting with a gradient of 10% to 75% EtOAc:hexane to yield the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:10][CH2:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: BrCCCCCCBr
Reactant: OCCCc1ccncc1
Product: BrCCCCCCOCCCc1ccncc1

Procedure:
From 4-pyridinepropanol (2.0 g) and 1,6-dibromohexane (8 ml), with a reaction time of 30 min. FCC eluting with hexane→ether gave the title compound as a colourless oil (1.1 g), t.l.c. (ether) Rf 0.45.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH2:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([NH:27][C:8]([C:7]2[C:2]([OH:1])=[N:3][C:4]([C:11]3[N:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[N:5][CH:6]=2)=[O:10])([CH3:25])[CH3:26])=[CH:22][CH:23]=1
Reactant: CC(C)(N)c1ccc(Br)cc1
Reactant: O=C(O)c1cnc(-c2cccnn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[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: CC(C)(NC(=O)c1cnc(-c2cccnn2)nc1O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxylic acid, 30-ie, (110 mg, 0.5 mmol), 2-(4-bromophenyl)propan-2-amine, 36-b, (70 mg, 0.32 mmol), HATU (290 mg, 0.76 mmol) and DIEA (82 mg, 0.64 mmol) in DMF (3 mL) was stirred at room temperature overnight. The mixture was washed with aqueous NH4Cl (15 mL) and extracted with EtOAc (30 mL). The organic layers were dried and concentrated in vacuo. The residue was washed with hexane to afford compound 36-c (80 mg, 57%). 1H NMR (300 MHz, CDCl3) δ11.62 (s, 1H), 9.55 (s, 1H), 9.41 (dd, J=1.5, 4.8 Hz, 1H), 9.00 (d, J=4.2 Hz, 1H), 8.63 (dd, J=1.5, 8.1 Hz, 1H), 7.78 (dd, J=5.1, 8.4 Hz, 1H)), 7.43 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 1.78 (s, 6H). LC-MS: (M+H)+ 414.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=5)=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N+:42]=5[O-:58])=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)ccn4)cc2)CCN3C(=O)C(F)(F)F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])cc2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methylpyridin-2-yl) methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.6 g) was dissolved in dichloromethane (20 ml), and to the solution was added 3-chloroperbenzoic acid (0.3 g) under ice-cooling and the mixture was stirred overnight at room temperature. An aqueous solution of sodium thiosulfate was added to the mixture. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine), to give 7-[4-(2-butoxyethoxy) phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.32 g) as colorless crystals.