Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]=[C:10]=[O:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:22]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N:17]=[CH:18]2>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]([NH:12][C:13]2[C:22]([C:23]([OH:32])([C:28]([F:31])([F:29])[F:30])[C:24]([F:25])([F:26])[F:27])=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][N:17]=[CH:18]3)=[O:11])=[CH:6][CH:7]=1
Reactant: Nc1c(C(O)(C(F)(F)F)C(F)(F)F)ccc2cnccc12
Reactant: O=C=NCc1ccc(Br)cc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Br)cc1)Nc1c(C(O)(C(F)(F)F)C(F)(F)F)ccc2cnccc12

Procedure:
The title compound was prepared using 1-bromo-4-(isocyanatomethyl)benzene, the product of Example 77A and the procedure described in Example 73B except that THF was used as solvent (white solid, 840 mg, 34%). MS (ESI+) m/z 376 (M+H)+; MS (ESI−) m/z 374 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 4.35 (d, 5.8, 2H), 7.12 (m, 1H), 7.18 (m, 2H), 7.40 (m, 1H), 7.91 (d, J 8.5, 1H), 7.99 (d, J 6.1, 1H), 8.24 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 8.88 (s, 1H), 9.44 (s, 1H); Anal. Calcd for C20H14BrF6N3O2: C, 46.00; H, 3.50; N, 11.23. Found: C, 54.61; H, 3.35; N, 11.14.
Reaction SMILES: Cl[C:2]1[C:6](Cl)=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:10].[Br:25]C1C=C(C(O)=O)NC=1C>>[Br:25][C:6]1[CH:2]=[C:3]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[O:10])[NH:4][C:5]=1[CH3:8]
Reactant: Cc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1Cl
Reactant: Cc1[nH]c(C(=O)O)cc1Br
Product: Cc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)cc1Br

Procedure:
Title compound was synthesized by an analogous method to Intermediate 2, starting from 4-bromo-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 18).
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:31])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]([C:28]#[N:29])=[N:15][C:14]=2[N:13]([CH3:30])[C:11]1=[O:12])(=[O:3])[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[C:1]([O:4][C@H:5]([CH3:31])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]([CH2:28][NH2:29])=[N:15][C:14]=2[N:13]([CH3:30])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(C#N)n2Cc2ccccc2)n(C)c1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(CN)n2Cc2ccccc2)n(C)c1=O

Procedure:
A suspension of (R)-1-(5-Acetoxyhexyl)-7-benzyl-8-cyano-3-methylxanthine (850 mg, 2.0 mmol) and 10% Pd on carbon (300 mg) in glacial acetic acid (60 ml) was treated with hydrogen gas (80 psi) on a Parr shaker for 3 hours. After filtering through a pad of celite, the filtrate was concentrated under reduced pressure to provide the acetic acid salt of (R)-1-(5-acetoxyhexyl)-8-aminomethyl-7-benzyl-3-methylxanthine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]#[N:22])[CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH:9]([NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH2:8][C:7]2=1.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]#[N:22])[CH:5]=[C:6]2[C:14]=1[N:13]([CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([F:23])[CH:25]=1)[C:12]1[CH2:11][CH2:10][CH:9]([NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH2:8][C:7]2=1
Reactant: Fc1cccc(CBr)c1
Reactant: CC(C)C(=O)NC1CCc2[nH]c3c(Cl)cc(C#N)cc3c2C1
Product: CC(C)C(=O)NC1CCc2c(c3cc(C#N)cc(Cl)c3n2Cc2cccc(F)c2)C1
Yield: 10 %

Procedure:
Prepare the title compound by essentially following the procedure as described in Example 96 with N-(8-chloro-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (Preparation 18) and 3-fluorobenzyl bromide, to obtain the title compound as a white solid in 10% yield. MS (ES): 424 (M+1), 422 (M−1); HPLC (Method A): Rt=3.18 (92%).
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]([CH2:9][CH2:10][NH2:11])=[CH:7][O:8][C:4]=2[CH:3]=1.O=[C:15]([CH3:28])[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[I:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]3[CH2:9][CH2:10][NH:11][C:15]([CH2:16][N:17]4[C:25](=[O:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]4=[O:27])([CH3:28])[C:7]=3[O:8][C:4]=2[CH:3]=1
Reactant: NCCc1coc2cc(I)ccc12
Reactant: CC(=O)CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(CN2C(=O)c3ccccc3C2=O)NCCc2c1oc1cc(I)ccc21
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a mixture of 2-(6-iodo-benzofuran-3-yl)-ethylamine (2.00 g, 6.97 mmol) and 2-(2-oxo-propyl)-isoindole-1,3-dione (4.25 g, 20.9 mmol) was added trifluoroacetic acid (8.00 mL, 104 mmol) and then heated at 80° C. After 16 h, additional ketone (3 eq) was added and heating continued. After a total of 3 days, the reaction mixture was basified (DCM-aq. NaHCO3) and the resulting precipitate was filtered, rinsed with DCM and dried to give an off-white solid. mp 302-304° C. dec.; MS m/z 473 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[N:16][C:17]([CH:20]([NH:22][C:23](=O)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:21])=[CH:18][N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:21][C:20]1[N:22]=[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:16]2[C:17]=1[CH:18]=[N:19][C:14]([NH:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=1)=[N:15]2
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3)nn2)cc(OC)c1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccccc4)n3n2)cc(OC)c1OC
Temperature: 25 °C
Yield: 9.4 %

Procedure:
To a solution of N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (150 mg, 0.38 mmol) in 1,2-dichloroethane (10 mL) was added phosphorus oxychloride (0.28 mL, 3.0 mmol). The mixture was heated to reflux for 24 hours. After cooling to room temperature, the excess phosphorus oxychloride was quenched with water and silica gel (0.5 g) was added to the reaction mixture, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexane (25:75) to ethyl acetate (100%) using a RediSep silica gel cartridge (4.2 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 5-methyl-7-phenyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.014 g) as an off-white solid. 1H NMR (CDCl3): δ8.78 (s, 1H), 8.43 (d, J=6.9 Hz, 2H), 7.49-7.35 (m, 3H), 6.94 (s, 1H), 6.68 (s, 2H), 3.83 (s, 3H), 3.81 (s, 6H), 2.59 (s, 3H). MS m/z 392 (M+1).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:7][O:6]1)[CH2:2][CH:3]=[CH2:4].[CH2:8]=[CH:9][CH2:10][CH2:11]CC>>[CH2:1]([CH:5]1[CH2:7][O:6]1)[CH2:2]/[CH:3]=[CH:4]/[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C=CCCC1CO1
Reactant: C=CCCCC
Product: CCCC/C=C/CCC1CO1

Procedure:
2-(But-3-enyl)oxirane (1.000 g, 10.2 mmol) and hex-1-ene (9.12 g, 102 mmol) were stirred at room temperature for 24 hr in a sealed scintillation vial with Zhan Catalyst-1 (0.057 g, 0.086 mmol). Solvent was removed under reduced pressure and the residue purified by column chromatography (0–10% EtOAc/n-hexane/silica) to give (±)-(E)-2-(oct-3-enyl)oxirane as a colorless oil. 1H NMR (CDCl3): δ 5.5–5.4 (m, 2H), 3.0–2.9 (m, 1H), 2.8–2.7 (m, 1H), 2.5–2.45 (m, 1H), 2.2–2.1 (m, 2H), 1.99 (q, 2H, J=5.7), 1.65–1.55 (m, 2H), 1.35–1.25 (m, 4H), 0.95–0.85 (m, 3H). Contains ca 20% (Z)-2-(oct-3-enyl)oxirane.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[CH3:40][O:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](Cl)=[O:47])=[CH:44][CH:43]=1>>[CH3:40][O:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:30][CH2:29]5)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:47])=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCCC(NC(=O)OC(C)(C)C)C(=O)N3C2)cc1
Yield: 26.8 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 4-methoxybenzoyl chloride (72 mg, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 33 mg (27%) of 18-(4-methoxybenzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.0% pure (HPLC), MS m/z 701 (M−H)−, HRMS: calcd. 703.3013 and found 703.3006 (M+H)+, mp 151-153° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:22])[C:9]([CH3:21])=[C:10]([C:11]3[CH:19]=[C:18]4[C:14]([CH2:15][CH2:16][N:17]4[CH3:20])=[CH:13][CH:12]=3)[C:3]=12.[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[N:25]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:22][N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([NH:32][S:29]([C:26]3[CH:27]=[CH:28][N:24]([CH3:23])[N:25]=3)(=[O:31])=[O:30])=[C:3]2[C:10]([C:11]2[CH:19]=[C:18]3[C:14]([CH2:15][CH2:16][N:17]3[CH3:20])=[CH:13][CH:12]=2)=[C:9]1[CH3:21]
Reactant: Cc1c(-c2ccc3c(c2)N(C)CC3)c2c(Br)ccnc2n1C
Reactant: Cn1ccc(S(N)(=O)=O)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1c(-c2ccc3c(c2)N(C)CC3)c2c(NS(=O)(=O)c3ccn(C)n3)ccnc2n1C
Temperature: 25 °C
Yield: 32.4 %

Procedure:
A mixture of 4-bromo-1,2-dimethyl-3-(1-methylindolin-6-yl)-1H-pyrrolo[2,3-b]pyridine (D28) (390 mg, 1.095 mmol), 1-methyl-1H-pyrazole-3-sulfonamide (D94) (265 mg, 1.642 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (95 mg, 0.164 mmol), cesium carbonate (1070 mg, 3.28 mmol) and Pd2(dba)3 (75 mg, 0.082 mmol) in 1,4-dioxane (10 mL) was refluxed for 7 hours. After cooled to RT, the reaction mixture was filtered through celite, washing with DCM and the resulting solution was evaporated to dryness. DCM was added to the residue and the resulting solid was filtered and then taken up in formic acid/DMSO (1:1), purified by MDAP (acidic condition) to give the title compound (155 mg). LCMS (A): m/z (M+H)+ 437, C22H24N6O2S requires 436 (acidic).
Reaction SMILES: O.O.O.[Ru:4](Cl)(Cl)[Cl:5].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[Cl-:20].[Li+].CC(C)=O>CN(C)C=O>[Cl-:5].[Cl-:20].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[Ru+2:4]
Reactant: Cl[Ru](Cl)Cl
Agent: [Cl-]
Agent: [Li+]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: O
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: [Ru+2]
Temperature: 15 °C
Reaction time: 24 h

Procedure:
A mixture of ruthenium trichloride trihydrate (2.5 g), 2,2' bipyridyl (3.0 g) and lithium chloride (5.0 g) was placed in 50 ml of DMF under nitrogen. This mixtrue was stirred and refluxed for 7 hours. The resulting purple/black solution was allowed to cool slowly to about 15° C. with continued stirring. 250 ml of acetone was then added and the flask stoppered under nigrogen. This solution was left at 0° C. for 24 hours. A black microcrystalline solid was recovered by filtration which was washed with water three times and diethyl ether three times.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[CH2:12][C:11]([CH3:15])=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13](=[O:14])[CH:12]([C:31](=[O:32])[NH:30][C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[C:11]([CH3:15])=[N:10]2)=[CH:7][CH:8]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1ccc(N2N=C(C)CC2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(N2N=C(C)C(C(=O)Nc3ccc(F)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the stirred suspension of 920 g of 1-(p-methoxyphenyl)-3-methyl-2-pyrazolin-5-one in 9,600 ml of toluene 460 g of triethylamine are added during 5 minutes, followed by 618 g of p-fluorophenylisocyanate. The mixture is stirred under nitrogen overnight at room temperature, cooled to 10° and combined with 5,000 ml of 1 N aqueous sodium hydroxide. The mixture is stirred for 15 minutes, the organic phase separated and extracted twice with 2,000 ml of 1 N aqueous sodium hydroxide again. The combined aqueous solutions are washed twice with 2,000 ml of diethyl ether each, cooled to 5° and acidified with 900 ml of concentrated hydrochloride acid during 30 minutes. The resulting suspension is stirred for 1 hour, filtered and the residue washed 6 times with 2,000 ml of water each. 1,364 g thereof are dissolved in 55,000 ml of boiling ethanol, the solution filtered hot and the filtrate stirred under nitrogen overnight at room temperature. The precipitate formed is filtered off, washed twice with 1,000 ml of cold ethanol each and recrystallized from ethanol again, to yield the 1-(p-methoxyphenyl)-3-methyl-4-(p-fluorophenylcarbamoyl)-2-pyrazolin-5-one melting at 255°-257° with decomposition; it is identical with that obtained according to Example 6.
Reaction SMILES: NC1C=CC=CC=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]2[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=1>>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C#Cc1ccc(F)cc1
Solvent: Nc1ccccc1
Product: COC(=O)c1ccc(N)cc1CCc1ccc(F)cc1

Procedure:
The “aniline” (compound 62) used in the preparation of compound 46 was synthesised from methyl 2-(2-(4-fluorophenyl)ethynyl)-4-nitrobenzoate by standard hydrogenation to give methyl 2-(4-fluorophenethyl)-4-aminobenzoate (compound 60). Compound 60 was hydrolysed to the corresponding benzoic acid (compound 61).
Reaction SMILES: [CH2:1]([CH:4]([CH2:14][CH2:15][CH3:16])[CH2:5][CH2:6][CH2:7][CH:8]1[CH2:13][O:12][CH2:11][CH2:10][NH:9]1)[CH2:2][CH3:3].C(N(CC)CC)C.[Cl-].C[O:26][C:27](=O)[CH2:28][CH2:29][CH2:30][C:31](O)=O.Cl.C(N(CC)CC)C>CCOCC.C1C=CC=CC=1>[CH2:14]([CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH:8]1[CH2:13][O:12][CH2:11][CH2:10][N:9]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][OH:26])[CH2:15][CH3:16]
Reactant: CCCC(CCC)CCCC1COCCN1
Reactant: COC(=O)CCCC(=O)O
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCCC(CCC)CCCC1COCCN1CCCCCO

Procedure:
A mixture of 8.0 grams (0.035 moles) of 3-(4-propyl-heptyl)-morpholine, 4 grams of triethylamine, 5.8 grams (0.035 moles) of glutaric acid-monomethylesterchloride and 100 ml. of benzene were refluxed for 3 hours. After cooling the triethylamine hydrochloride formed was removed by filtration and the benzene solution was directly admixed with 12 grams of lithium aluminum hydride in 500 ml of ether. The reaction mixture was refluxed for 8 hours and decomposed by slow addition of water and sodium hydroxide. The precipitate was filtered off. The ether solution was dried and evaporated to dryness and the residue was distilled at 144°-146° C./ 0.01 mm Hg.; yield 9.8 grams (89%). The base obtained was dissolved in ether and the hydrochloride precipitated with hydrochloric acid in ethanol. After recrystallization from ethylacetate/ether, the melting point was 59°-60° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=O)[CH:6]=[CH:5][N:4]=1.[C:20]([O:24][C:25]([N:27]1[CH2:36][C:35]([CH3:38])([CH3:37])[C:34]2[C:29](=[CH:30][C:31]([NH2:39])=[CH:32][CH:33]=2)[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:20]([O:24][C:25]([N:27]1[CH2:36][C:35]([CH3:38])([CH3:37])[C:34]2[C:29](=[CH:30][C:31]([NH:39][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10][CH2:9][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([NH:2][CH3:1])[N:8]=3)=[CH:32][CH:33]=2)[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C(C)(C)C1
Reactant: CNc1nccc(CNc2ccccc2C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nccc(CNc2ccccc2C(=O)Nc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3(C)C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-[(2-methylamino-pyrimidin-4-ylmethyl)-amino]-benzoic acid (Step C, 0.31 g, 1.20 mmol), 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.33 g, 1.20 mmol), TBTU (0.43 g, 1.32 mmol), and DIEA (0.31 mL, 1.80 mmol) in 10 mL of DMF was stirred at RT for 2 h. The mixture was partitioned between EtOAc and Na2CO3 (aq). The organic layer was washed with water, brine, dried with MgSO4, filtered, condensed, and the residue was purified by flash column chromatography (0 to 30% of EtOAc in CH2Cl2). The titled compound was obtained as a light yellowish solid. MS (ES+): 517.4 (M+H)+. Calc'd for C29H36N6O3-516.63
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([CH2:6][C:7]3([C:13]42[N:19]=[C:18]([NH2:20])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[F:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([C:2]2[CH:15]=[C:14]3[C:5]([CH2:6][C:7]4([C:13]53[N:19]=[C:18]([NH2:20])[C:17]([CH3:21])=[N:16]5)[CH2:8][CH2:9][O:10][CH2:11][CH2:12]4)=[CH:4][CH:3]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCOCC1
Product: CC1=NC2(N=C1N)c1cc(-c3ccc(F)c(Cl)c3)ccc1CC21CCOCC1
Yield: 42 %

Procedure:
The title compound was synthesized as described for Example 26a in 42% yield, starting from 6′-bromo-5-methyl-2″,3″,5″,6″-tetrahydro-3′H-dispiro[imidazole-2,1′-indene-2′,4″-pyran]-4-amine (Example 25, 75 mg, 0.22 mmol) and 3-chloro-4-fluorobenzeneboronic acid (45.1 mg, 0.26 mmol); 1H NMR (400 MHz, DMSO-d6) δ ppm 7.72 (dd, 1H), 7.52 (m, 2H), 7.42 (m, 2H), 6.80 (d, 1H), 6.60 (br. s, 1H), 3.66 (m, 2H), 3.48 (t, 1H), 3.40 (m, 1H), 3.20 (m, 1H), 3.07 (m, 1H), 2.19 (s, 3H), 1.71 (td, 1H), 1.23 (m, 3H); MS (ES+) m/z 398 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][C@@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.I.[NH2:37][C:38]1[C:39]([C:46]([NH:48][C:49](=[NH:52])SC)=[O:47])=[N:40][C:41]([Cl:45])=[C:42]([NH2:44])[N:43]=1>C(O)C>[C:23]([O:22][C:20]([NH:19][C@H:15]([CH2:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:49]([NH2:52])=[N:48][C:46]([C:39]2[C:38]([NH2:37])=[N:43][C:42]([NH2:44])=[C:41]([Cl:45])[N:40]=2)=[O:47])=[CH:7][CH:8]=1)[C:16]([OH:18])=[O:17])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCc1ccc(CCCCN)cc1)C(=O)O
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](CCCc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1)C(=O)O
Temperature: 65 °C
Yield: 74.7 %

Procedure:
The compound 280 (0.077 g, 0.211 mmol) was mixed with ethanol (5 mL). The mixture was heated at 65° C. for 15 min to achieve complete dissolution. To the clear solution were sequentially added diisopropylethylamine (0.184 mL, 1.056 mmol) and 1-(3,5-diamino-6-chloropyrazinoyl)-2-methylisothiourea hydriodide (0.99 g, 0.254 mmol). The mixture was heated at 65° C. for an additional three hours. It was then concentrated under vacuum. The residue was chromatographed over silica gel, eluting with a mixture of concentrated ammonium hydroxide (0-2.2%), methanol (0-22%) and dichloromethane (100-75.8%) to afford the product 290 (0.091 g, 75%) as a yellow solid. 1H NMR (300 MHz, CD6OD): δ 1.44 (s, 9H), 1.58-1.84 (m, 8H), 2.54-2.68 (m, 4H), 3.34-3.42 (m, 2H), 4.02 (m, 1H), 7.08 (s, 4H). m/z (APCI) 577 [C26H37ClN8O5+H]+.
Reaction SMILES: [CH3:1][O-].[Na+].[SH:4][C:5]1[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]([C:15]([O:17][CH2:18]C)=[O:16])=[C:8]([C:10]([O:12][CH2:13]C)=[O:11])[N:9]=1.IC>CO>[CH3:1][S:4][C:5]1[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]([C:15]([O:17][CH3:18])=[O:16])=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1
Reactant: CCOC(=O)c1nc(S)n(-c2ccccc2)c1C(=O)OCC
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: COC(=O)c1nc(SC)n(-c2ccccc2)c1C(=O)OC
Reaction time: 8 h
Yield: 80 %

Procedure:
Sodium methoxide (1.8 g; 0.033 mol) was slowly added to a suspension of diethyl 2-mercapto-1-phenyl-4,5-imidazoledicarboxylate (10 g; 0.031 mol) in absolute methanol (100 mL) then iodomethane (5 g; 0.035 mol) was added. The mixture was allowed to stir overnight, additional iodomethane (5 g; 0.035 mol) was added and the mixture was stirred for 1 hour. The methanol was removed in vacuo and ice-cold water was added to the residue. The mixture was filtered, the collected solid was washed with water and dried to give 7.6 g (80%) of pure dimethyl 2-(methylthio)-1-phenyl-4,5-imidazoledicarboxylate (mp 121°-122° C).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:26][O:27][CH2:28][CH2:29]Br.[H-].[Na+]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][N:22]([CH2:29][CH2:28][O:27][CH3:26])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COCCBr
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: COCCN1C[C@@H](C)n2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O
Yield: 26 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), 2-bromoethyl methyl ether and sodium hydride, to give the desired product as a light yellow oil (26%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[N:11]([CH:17]([CH3:19])[CH3:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:29]=[O:30]>>[CH2:1]([O:8][C:9]1[C:13]([CH:29]=[O:30])=[C:12]([CH:14]([CH3:15])[CH3:16])[N:11]([CH:17]([CH3:19])[CH3:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CC(C)c1cc(OCc2ccccc2)nn1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1c(C=O)c(OCc2ccccc2)nn1C(C)C
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-benzyloxy-1,5-diisopropyl-1H-pyrazole (0.44 g) in N,N-dimethylformamide (3 mL) was added phosphorus oxychloride (0.31 g) at 80° C., and the mixture was stirred at 80° C. for 30 minutes. After the reaction mixture was cooled to room temperature, a sodium hydroxide aqueous solution (1 mol/L) was added to the reaction mixture. The mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give the title compound (0.42 g).