Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:26]=[C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37]C(C3C=CSC=3)=O)[CH:32]=2)=[O:28])[CH:24]=[C:23]([CH3:45])[C:5]=1[C:6]([NH:8][C@H:9]([C:19]([O:21]C)=[O:20])[CH2:10][NH:11][C:12]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)=[O:13])=[O:7]>CO>[Cl:3][C:4]1[CH:26]=[C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=2)=[O:28])[CH:24]=[C:23]([CH3:45])[C:5]=1[C:6]([NH:8][C@H:9]([C:19]([OH:21])=[O:20])[CH2:10][NH:11][C:12]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)=[O:13])=[O:7]
Reactant: COC(=O)[C@H](CNC(=O)c1ccsc1)NC(=O)c1c(C)cc(C(=O)NCc2cccc(OC(=O)c3ccsc3)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(=O)NCc2cccc(O)c2)cc(Cl)c1C(=O)N[C@@H](CNC(=O)c1ccsc1)C(=O)O
Reaction time: 8 h
Yield: 59.3 %

Procedure:
An aqueous solution of sodium hydroxide (1 M; 0.5 mL, 0.5 mmol) was added to a solution of N-[2-chloro-4-[[[[3-[(thiophene-3-carbonyl)oxy]phenyl]methyl]-amino]carbonyl]-6-methylbenzoyl]-3-[(thiophene-3-carbonyl)amino]-L-alanine, methyl ester (160 mg, 0.25 mmol) in methanol (2 mL). The solution was allowed to stir overnight and then concentrated. The residue was purified by HPLC and lyophilized to give N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-6-methylbenzoyl]-3-[(thiophene-3-carbonyl)amino]-L-alanine (76.5 mg, 59%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH:18]1OCC[O:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>O1CCCC1>[CH2:23]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH:18]=[O:19])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=[N+]([O-])c1cccc(N(Cc2ccccc2)Cc2ccccc2)c1C1OCCO1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=Cc1c(N(Cc2ccccc2)Cc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 40A (1.88 g, 4.83 mmoles) in tetrahydrofuran (30 mL) was treated with an aqueous solution of 2N sulfuric acid (1.24 mL) and allowed to stirr overnight at 65° C. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate, and concentrated under reduced pressure. The residue was mixed with diethylether and washed with water, brine, dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to provide the title compound. MS (ESI+) at m/z 347 (M+H)+.
Reaction SMILES: C([N:8]1[C:12]([CH3:13])=[C:11]([CH2:14][CH:15]2[C:31](=[O:32])[N:19]3[C:20]4[C:25]([C:26]([CH2:27]N(C)C)=[C:18]3[CH2:17][CH2:16]2)=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:10]=[CH:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C.O.O1CCCC1>[CH3:27][C:26]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]2[C:31](=[O:32])[CH:15]([CH2:14][C:11]3[N:10]=[CH:9][NH:8][C:12]=3[CH3:13])[CH2:16][CH2:17][C:18]=12
Reactant: Cc1c(CC2CCc3c(CN(C)C)c4ccccc4n3C2=O)ncn1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1[nH]cnc1CC1CCc2c(C)c3ccccc3n2C1=O
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
A mixture of 7-[(1-benzyl-5-methyl-1H-imidazol-4-yl)methyl]-10-[(dimethylamino)methyl]-8,9-dihydropyrido[1,2-a]indol-6(7H)-one (215 mg), ammonium formate (318 mg), 10% palladium on carbon (107 mg), water (1 ml), ethanol (2 ml), and tetrahydrofuran (1 ml) was heated at 75° C. for 40 minutes and then cooled. Ammonium formate (300 mg), 10% palladium on carbon (110 mg), water (1 ml), and ethanol (2 ml) were added successively to the reaction mixture. Heating at 75° C. was continued for further 1 hour 20 minutes. After cooling, the reaction mixture was filtered and the residue was washed with 10% methanol-chloroform. The filtrate was evaporated in vacuo. The residue was diluted with water and extracted three times with 10% methanol-chloroform. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfte, and evaporated in vacuo. Silica gel column chromatography of the residue using 5% methanol-chloroform as eluent gave 8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (108 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([Cl:10])[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].[Br:15]N1C(=O)CCC1=O>C(Cl)Cl>[OH:1][C:2]1[C:9]([Br:15])=[C:8]([Cl:10])[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1cc(C=O)c(O)cc1Cl
Solvent: ClCCl
Product: CC(C)(C)c1cc(C=O)c(O)c(Br)c1Cl
Yield: 81.3 %

Procedure:
A solution of 1.84 g (8.65 mmol) of 2-hydroxy-4-chloro-5-(1,1-dimethylethyl)benzaldehyde and 1.85 g (10.4 mmol) of N-bromosuccinimide in 30 ml of methylene chloride was stirred overnight at ambient temperature. The solvent was evaporated and the residue was partitioned between water and hexane. The organic phase was dried and evaporated. The residue was chromatographed on 150 g of silica gel using a gradient from 1:99 to 5:95 (v/v) of ether:hexane as eluent. There was obtained 2.05 g (7.03 mmol, 81%) of 2-hydroxy-3-bromo-4-chloro-5-(1,1-dimethylethyl)benzaldehyde after crystallization from hexane; mp 92°-94° C.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[N:34]1([CH2:40][C:41]2[CH:42]=[C:43]([C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([CH2:53][NH2:54])[CH:48]=3)[CH:44]=[CH:45][CH:46]=2)[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C.[CH3:64][N:65]([CH3:76])[C:66]1[CH:71]=[CH:70][C:69]([CH2:72][C:73](O)=[O:74])=[CH:68][CH:67]=1>C(Cl)(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:76][N:65]([CH3:64])[C:66]1[CH:71]=[CH:70][C:69]([CH2:72][C:73]([NH:54][CH2:53][C:49]2[CH:48]=[C:47]([C:43]3[CH:44]=[CH:45][CH:46]=[C:41]([CH2:40][N:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)[CH:42]=3)[CH:52]=[CH:51][CH:50]=2)=[O:74])=[CH:68][CH:67]=1
Reactant: CN(C)c1ccc(CC(=O)O)cc1
Reactant: NCc1cccc(-c2cccc(CN3CCNCC3)c2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CN(C)c1ccc(CC(=O)NCc2cccc(-c3cccc(CN4CCNCC4)c3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.1 %

Procedure:
A mixture of PyBOP (0.08 mmol in 200 mL of DMF), {[3′-(1-piperazinylmethyl)-3-biphenylyl]methyl}amine (44 mmol in 200 mL of DMF) and DIPEA (30 mL) were added to [4-(dimethylamino)phenyl]acetic acid (0.07 mmol). The resulting mixture was stirred for 16 hours at room temperature, then the solvent was removed under vacuum. The residue was dissolved in methanol and purified by loading onto a SPE cartridge (SCX, 500 mg), washing with MeOH, and eluting with a 2 M solution of NH3 in MeOH. The NH3 fraction was collected and evaporated under vacuum to give a gum which was dissolved in 1:1 CHCl3/TFA (0.5 mL). After stirring for 2 hours, the solvent was removed under vacuum and the residue was dissolved in MeOH. The free base of the compound was obtained by loading the solution onto a SPE cartridge (SCX, 500 mg), washing with MeOH, and eluting with 2M NH3/MeOH. The ammonia fraction was collected and the solvent was removed under vacuum to give the title compound (14.6 mg). LC/MS: m/z, 443 (M+H), 2.21 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-:3])=[O:2].CN(C)C=O>C1(C)C=CC=CC=1>[C:6]([O:14][C:13](=[O:15])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[CH:7]=1)([CH3:13])([CH3:7])[CH3:5]
Reactant: O=C(O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Reaction time: 0.75 h
Yield: 248.8 %

Procedure:
To a suspension of 5-nitro-isophthalic acid (5.0 g, 23.7 mmol) in dry toluene (100 ml) at 110° C. was added dimethylformamide di-t-butylacetale (3.4 ml, 71 mmol) drop wise over 60 min. Heating was continued for 45 min and the reaction mixture was left at Rt over night. The precipitated starting material was removed by filtration. The filtrate was concentrated to give a yellow oil (7.88 g). This was purified by flash chromatography using EtOAc/Hept 1:2 and EtOAc/Hept 1:2+5% AcOH in two portions to give the title compound in 38% yield (2.38 g)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:22][C:23]1[CH:24]=[C:25]([C:29]2[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=2)[CH:26]=[N:27][CH:28]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22][C:23]2[CH:24]=[C:25]([C:29]3[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=3)[CH:26]=[N:27][CH:28]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2)CC1
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Product: COc1cc(-c2cncc(CN(c3ccccc3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-phenylaminopiperidine (553 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[C:6](=[O:7])[CH:5]=[CH:4][CH2:3]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([F:19])[CH:11]=1.C([O-])(=O)C.[Na+].[Sb](Cl)(Cl)Cl>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)(=O)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:4]2[CH2:5][C:6](=[O:7])[C:2]([CH3:8])([CH3:1])[CH2:3]2)=[C:12]([F:19])[CH:11]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: CC1(C)CC=CC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl[Sb](Cl)Cl
Solvent: CC(=O)O
Product: CC1(C)CC(c2ccc(Cl)cc2F)CC1=O
Yield: 87.2 %

Procedure:
A solution of 5,5-dimethylcyclopent-2-en-1-one (42.0 g, 343.15 mmol), 4-chloro-2-fluorophenylboronic acid (94.47 g, 514.72 mmol), sodium acetate (56.30 g, 686.30 mmol), acetic acid (1130 mL), Pd(OAc)2 (7.70 g, 34.31 mmol), and antimony trichloride (7.83 g, 34.31 mmol) are stirred at ambient temperature for 16 hours. The solvent is evaporated to low volume and the residual acetic acid is removed using toluene. MTBE (500 mL) is added and the resulting precipitate is filtered off and discarded. The MTBE solution is washed with water (500 mL), aq. NaHCO3 (2×300 mL), dried over MgSO4, filtered, and concentrated to dryness. The residue is purified by silica gel flash chromatography, eluting with hexane to hexane 10% MTBE to give the title compound (72 g, 87%). 1H NMR (300.16 MHz, CDCl3) δ 7.21-7.06 (m, 3H), 3.67-3.59 (m, 1H), 2.81-2.72 (m, 1H), 2.41-2.31 (m, 1H), 2.21 (ddd, J=12.6, 6.3, 2.2 Hz, 1H), 1.89 (t, J=12.3 Hz, 1H), 1.159 (s, 3H), 1.137 (s, 3H).
Reaction SMILES: [N+]([O-])(O)=[O:2].[CH3:5][C:6]1([CH3:15])[CH2:11][CH2:10][CH2:9][CH:8]([CH3:12])[CH:7]1[CH:13]=[O:14]>>[CH3:15][C:6]1([CH3:5])[CH2:11][CH2:10][CH2:9][CH:8]([CH3:12])[CH:7]1[C:13]([OH:2])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: CC1CCCC(C)(C)C1C=O
Product: CC1CCCC(C)(C)C1C(=O)O
Temperature: 55 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
In a 300-ml 4-necked flask equipped with a condenser, a thermometer, a dropping funnel, and a stirrer was placed 39 g of nitric acid (aqueous 60% solution), and the temperature was raised to 55° C. Then, 93 g (0.60 mole) of 2,2,6-trimethylcyclohexanecarbaldehyde [composition: 90.2% of the trans-form, 9.8% of the cis-form] synthesized in Synthesis Example 6-A) was added dropwise thereto over a period of 2 hours. Thereafter, the reaction was carried out for 3 hours at the same temperature, and the reaction mixture obtained was washed with of 100 g of toluene and 100 g of water, followed by separating an organic layer from an aqueous layer. After further washing thrice the organic layer with 100 g of a saturated aqueous sodium chloride solution, the organic layer formed was separated from an aqueous layer. The toluene was distilled off from the organic layer by an evaporator under reduced pressure to provide 101 g of crude 2,2,6-trimethylcyclohexanecarboxylic acid (5) [composition: 90.5% of the trans-form, 9.5% of the cis-form].
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10](=[O:29])[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:28])[NH:24][CH:25]3[CH2:27][CH2:26]3)=[CH:19][CH:18]=2)[N:16]=1)=[O:4].CO.[Li+].[OH-].CC(O)=O>C1COCC1>[CH:25]1([NH:24][C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:15]3[N:16]=[C:12]([NH:11][C:10]([C@@H:6]4[CH2:7][CH2:8][CH2:9][C@H:5]4[C:3]([OH:4])=[O:2])=[O:29])[S:13][CH:14]=3)=[CH:18][CH:19]=2)=[O:28])[CH2:26][CH2:27]1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@@H]3CCC[C@H]3C(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Rac-trans-2-[4-(4-Cyclopropylcarbamoyl-phenyl)-thiazol-2-ylcarbamoyl]-cyclopentanecarboxylic acid methyl ester (100 mg) was dissolved in THF:MeOH:H20 (2:2:1, 5 mL) and treated with LiOH (10 eq. 45 mg) and stirred at room temperature for 15 hours. The mixture was neutralized with HOAc, and the solvents removed. The resulting mixture was redissolved in 5 ml of 90% DMF, 10% water with 0.1% TFA and purified by reverse phase HPLC to give the product. MS: 400.5 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]2[C:19](OC)=[N:18][S:17](=[O:22])[N:16]=2)[N:9]=1)[CH3:3].COC1C(OC)=NS(=O)[N:26]=1.N>>[NH2:26][C:19]1[C:15]([NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]2[N:9]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[S:6][CH:7]=2)=[N:16][S:17](=[O:22])[N:18]=1
Reactant: COC1=NS(=O)N=C1NCCSCc1csc(CN(C)C)n1
Reactant: COC1=NS(=O)N=C1OC
Agent: N
Product: CN(C)Cc1nc(CSCCNC2=NS(=O)N=C2N)cs1

Procedure:
When a methanolic solution of 3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1-oxide [prepared from 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide by the general procedure described in Example 34, Step F] is reacted with anhydrous ammonia according to the general procedure described in Example 35, the title compound is thereby produced.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([OH:28])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29](OC1C=CC=CC=1/C=C/C1C=CC(C(OC)=O)=C(OC)C=1)C1C=CC=CC=1.C(OC1C=CC=CC=1/C=C/C1C=CC(C(OC)=O)=C(O)C=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([O:28][CH3:29])[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CCCc2ccccc2OCc2ccccc2)cc1O
Reactant: COC(=O)c1ccc(/C=C/c2ccccc2OCc2ccccc2)cc1OC
Agent: COC(=O)c1ccc(/C=C/c2ccccc2OCc2ccccc2)cc1O
Product: COC(=O)c1ccc(CCCc2ccccc2OCc2ccccc2)cc1OC

Procedure:
Methyl 4-[3-(2-benzyloxyphenyl)-propyl]-2-methoxybenzoate was synthesised from methyl 4-[3-(2-benzyloxyphenyl)-propyl]-2-hydroxybenzoate (prepared as described in Example 15) as described in Example 14 for the synthesis of methyl 4-[2-(2-benzyloxyphenyl)-(E)-ethenyl]-2-methoxybenzoate from methyl 4-[2-(2-benzyloxyphenyl)-(E)-ethenyl]-2-hydroxybenzoate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:32])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.C1(C)C=CC(S([C:47]#[N:48])(=O)=O)=CC=1.[NH4+].[Cl-]>C1COCC1.CCOCC.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16]([C:47]#[N:48])=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:32])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: CCc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)c(F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCc1nc(C#N)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)c(F)c1
Temperature: -78 °C
Reaction time: 0.05 h

Procedure:
A cooled (−78° C.) solution of 3-ethyl-8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-1-iodo-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.040 g; 1.833 mmol) in anhydrous THF (50 ml) was treated dropwise with 1.6M n-BuLi in hexanes (1.6 ml; 2.560 mmol). The resulting reaction mixture was further stirred at −78° C., under nitrogen, for 3 min., and a solution of para-toluenesulfonyl cyanide (0.576 g; 3.025 mmol) in anhydrous THF (5 ml) was then added dropwise. Stirring at −78° C. was continued for 20 min. before aq. sat. NH4Cl (2 ml) was added. The resulting mixture was allowed to warm-up to rt, and water (50 ml), followed by ether (50 ml) were added. The organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH, 25/1) afforded 1-cyano-3-ethyl-8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a pale yellow solid (0.233 g; 27%). LC-MS: tR=1.12 min.; [M+H]+=467.23 g/mol.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N:20]4[C:32]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:26]5[C:21]4=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:15]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)Cl.CN([CH:41]=[O:42])C.O=P(Cl)(Cl)Cl.[OH-].[K+].O>ClCCCl.CN(C=O)C>[CH:10]1[C:11]2[N:12]([C:14]3[N:15]=[C:16]([N:20]4[C:32]5[CH:31]=[CH:30][C:29]([CH:41]=[O:42])=[CH:28][C:27]=5[C:26]5[C:21]4=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH:17]=[CH:18][CH:19]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)C=O
Reactant: c1cc(-n2c3ccccc3c3ccccc32)nc(-n2c3ccccc3c3ccccc32)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1ccc2c(c1)c1ccccc1n2-c1cccc(-n2c3ccccc3c3ccccc32)n1
Temperature: 110 °C
Reaction time: 72 h
Yield: 40.3 %

Procedure:
To a solution of 2,6-di(carbazol-9-yl)pyridine, prepared above in step 1, (10.0 g, 24.4 mmol) in 1,2-dichloroethane (80.0 ml) was slowly added POCl3/DMF (32.0 g/16.0 g). POCl3/DMF was made by the addition of POCl3 into DMF at 0° C. at room temperature under nitrogen atmosphere and stirring. After the addition of POCl3/DMF, the reaction mixture was heated to 110° C. and kept at this temperature for 72 hours. After cooling, the reaction mixture was slowly added into an ice-bath cooled KOH water solution (500.0 ml of water with 100 g of KOH). After addition, the reaction mixture was stirred for 60 minutes. The water solution was extracted with ethyl acetate (3×100 ml). The organic extracted solution was washed with water until a pH=7 was obtained. The removal of solvent, crude product was purified by silica gel column with dichloromethane:hexanes:ethyl acetate (5:4.5:0.5) as the solvent mixture. After removal of the solvent mixture, the product was recrystallized from THF/water to give 4.3 g (40.3%) of pure product.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[NH:14][CH2:13][CH2:12][NH:11]2)=[C:5]([CH3:15])[CH:4]=1.[BrH:16]>>[BrH:16].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[NH:11][CH2:12][CH2:13][NH:14]2)=[C:5]([CH3:15])[CH:4]=1
Reactant: COc1ccc(N=C2NCCN2)c(C)c1
Agent: Br
Product: Cc1cc(O)ccc1N=C1NCCN1

Procedure:
A solution of 2-(4-methoxy-2-methylphenylimino)imidazolidine (2.05 g, 10 mmoles) in 48% hydrobromic acid (20 ml) is heated with stirring in an oil bath at 110°.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].I[CH2:12][CH2:13][CH2:14][CH3:15]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH2:13][CH2:14][CH3:15])[N:5]=1)([O-:3])=[O:2]
Reactant: CCCCI
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCn1ccc([N+](=O)[O-])n1
Reaction time: 16 h
Yield: 73.7 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 100 mg, 0.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (42 mg, 1.06 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min before 1-iodo-butane (121 μL, 1.06 mmol) was added. The reaction continued to stir under nitrogen for 4 h. The reaction was stored at −25° C. for 16 h. The solution was diluted with ethyl acetate (30 mL), washed with water (2×10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 25% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-nitro-1-butyl-1H-pyrazole (111 mg, 62%) as a clear oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.CC([O-])(C)C.[Na+]>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]>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][N:15]=[C:16]([N:17]5[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]5)[C:11]4=[N:10][CH:9]=3)[N:7]=2)=[CH:27][CH:26]=1
Reactant: CN1CCN(c2nccn3c(-c4cccc(Br)n4)cnc23)CC1
Reactant: NCc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CN1CCN(c2nccn3c(-c4cccc(NCc5ccc(Cl)cc5)n4)cnc23)CC1
Temperature: 100 °C

Procedure:
A mixture of 3-(6-bromo-pyridin-2-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 39 supra) (0.373 g, 1.0 mmol), 4-chloro-benzylamine (0.14 g, 1.0 mmol), Pd2(dba)3 (60 mg), Davephos (80 mg), NaOtBu (140 mg, 1.46 mmol) suspended in dioxane (25 mL). The solution was bubbled with N2 for several minutes and then heated under N2 at 100° C. for 15 hours. The solution was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The obtained crude product was purified by preparative-HPLC to give (4-chloro-benzyl)-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-amine; hydrochloride. (Yield 31 mg, 7.1%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[NH:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([F:17])=[CH:11][N:10]=2)=[O:5])[CH3:2].[N:19]1([C:25]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[NH:8][C:9]2[C:14]([C:15]=1[N:22]1[CH2:23][CH2:24][N:19]([C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[O:26])[CH2:20][CH2:21]1)=[CH:13][C:12]([F:17])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: CCOC(=O)c1c(Cl)c2cc(F)cnc2[nH]c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2[nH]c1=O

Procedure:
This compound was prepared from 4-chloro-6-fluoro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (78) and piperazine-1-yl-thiophene-2-yl-methanone according to general procedure E. Yield 3.16 g (66%), MP 124-133° C.; 1H-NMR (DMSO-d6): δ 1.26 (t, J=7.2 Hz, 3H), 3.11 (m, 4H), 3.88 (m, 4H), 4.28 (q, J=7.2 Hz, 2H), 7.15 (dd, J=3.6, 4.8 Hz, 1H), 7.45 (dd, J=1.2, 3.6 Hz, 1H), 7.79 (dd, J=1.2, 4.8 Hz, 1H), 8.05 (dd, J=2.8, 8.0 Hz, 1H), 8.63 (d, J=2.8 Hz, 1H) 12.40 (s, 1H); EIMS: 431 (M+1).