Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.Cl.Cl.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][CH:26]1[NH:27][CH2:28][CH2:29][N:24]([C:21]2[CH:20]=[CH:19][C:18]([CH3:17])=[CH:23][CH:22]=2)[CH2:25]1.[CH3:2][C:3]([CH3:8])([CH3:7])[CH:4]=[O:5]
Reactant: CC(C)(CBr)C(=O)O
Reactant: Cc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C=O
Product: Cc1ccc(N2CCNC(Br)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
3-Bromo-2,2-dimethylpropionic acid (10.0 g, 55.3 mmol) was dissolved in DCM (60 mL). Oxalyl chloride (7.20 mL, 82.9 mmol) was added slowly over 10 minutes. The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was dissolved in DCM (40 mL) and added to a solution of 4-methylphenyl-piperazine dihydrochloride (13.76 g, 55.3 mmol) and DIPEA (33.0 mL, 193.4 mmol) in DCM (100 mL) at 0° C. The reaction mixture was allowed to warm to room temperature over 1 hour and then stirred at room temperature for 16 hours. The reaction mixture was washed with 10% citric acid solution (2×100 mL), dried (MgSO4) and concentrated in vacuo to give 3-bromo-1-(4-methylphenyl)piperazine-2,2-dimethylpropan-1-one (9.62 g, 52%) as a white solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=3)[N:12]=[C:11]([C:21](O)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:45]3[CH2:49][C:48](=[O:50])[NH:47][CH2:46]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=3)[N:12]=[C:11]([C:21]([N:45]3[CH2:49][C:48](=[O:50])[NH:47][CH2:46]3)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cncc(Cl)c2)n1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cncc(Cl)c3)n2)CN1

Procedure:
75 mg (0.21 mmol) of the compound of Example 26A is reacted analogously to the synthesis of the compound of Example 1 with 29 mg (0.23 mmol) of 4-imidazolinone-hydrochloride. 74 mg (82% of theory) of the title compound is obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[C:8]([OH:15])=[CH:7][C:5]=2[N:6]=1.[CH3:16][C:17]1[NH:18][C:19]2[C:25]([OH:26])=[C:24]([C:27]([O:29][CH3:30])=[O:28])[CH:23]=[CH:22][C:20]=2[N:21]=1.[C:31]([O:35][C:36](O[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:37])([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>C1COCC1>[C:31]([O:35][C:36]([N:6]1[C:5]2[CH:7]=[C:8]([OH:15])[C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:4]=2[N:3]=[C:2]1[CH3:1])=[O:37])([CH3:34])([CH3:33])[CH3:32].[C:42]([O:41][C:39]([N:21]1[C:20]2[CH:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([OH:26])[C:19]=2[N:18]=[C:17]1[CH3:16])=[O:40])([CH3:43])([CH3:44])[CH3:45]
Reactant: COC(=O)c1cc2[nH]c(C)nc2cc1O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc2nc(C)[nH]c2c1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2nc(C)n(C(=O)OC(C)(C)C)c2cc1O
Product: COC(=O)c1ccc2c(nc(C)n2C(=O)OC(C)(C)C)c1O
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a mixture of 2-methyl-6-hydroxy-5-methoxycarbonylbenzimidazole and 2-methyl-4-hydroxy-5-methoxycarbonylbenzimidazole (7.2 g) in THF (50 mL) was added di-tert-butyldicarbonate (7.6 g) and triethylamine (5 mL). After stirring at 50° C. for 6 hours the solvent was removed and the residue was triturated with ethyl acetate and filtered to afford 1-tert-butoxycarbonyl-2-methyl-6-hydroxy-5-methoxycarbonylbenzimidazole and 1-tert-butoxycarbonyl-2-methyl-4-hydroxy-5-methoxycarbonylbenzimidazole.
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[OH:12])=[O:4].[C:13](OCC)(=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>C(O)C>[OH:11][C:9]1[CH:10]=[C:5]2[C:6](=[CH:7][CH:8]=1)[O:12][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:2][C:3]2=[O:4]
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2cc(O)ccc2o1
Temperature: 25 °C

Procedure:
1.1 3.25 g of sodium are dissolved in portions in 300 ml of ethanol with stirring. A solution of 4.3 g of 2,5-dihydroxyacetophenone and 15.5 ml of diethyl oxalate in 25 ml of ethanol is subsequently added dropwise. The reaction mixture is subsequently heated at 80° for 3 hours. The mixture is cooled to room temperature, and 10 ml of 32% HCl are added dropwise. The mixture is heated at 90° for 30 minutes and cooled, and the solvent is removed. Conventional work-up gives 5.9 g of 6-hydroxy-2-ethoxycarbonyl-chromone (“AA”).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:25][N:26]([CH3:28])[CH3:27])=[CH:8][N:9]2[Si:12]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:5][CH:4]=1.C([Li])(C)(C)C.[Cl:34]C(Cl)(Cl)C(Cl)(Cl)Cl>CCOCC>[Cl:34][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[C:10]2[C:6]=1[C:7]([CH2:25][N:26]([CH3:28])[CH3:27])=[CH:8][N:9]2[Si:12]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:13]([CH3:14])([CH3:15])[CH3:16])[C:17]([CH3:19])([CH3:18])[CH3:20]
Reactant: COc1ccc2c(CN(C)C)cn([Si](C(C)(C)C)(C(C)(C)C)C(C)(C)C)c2c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: COc1cc(Cl)c2c(CN(C)C)cn([Si](C(C)(C)C)(C(C)(C)C)C(C)(C)C)c2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88.6 %

Procedure:
To a stirred solution of (6-methoxy-1-tri-tert-butylsilanyl-1H-indol-3-ylmethyl)-dimethylamine (0.2 g, 0.56 mmol) in anhydrous ether (20 ml) at −78° C. was added tert-butyllithium (43 mg, 0.67 mmol, 1.7M in pentane) dropwise. After being stirred for 20 min, the mixture was allowed to warm to 0° C. and was stirred for one hour. The mixture was then re-cooled to −78° C., and a solution of hexachloroethane (0.2 g, 0.84 mmol) in anhydrous ether (10 ml) was added over 10 min. The reaction mixture was warmed to room temperature and stirring was continued for another 1.5 hour before quenching with saturated ammonium chloride solution. After extracting into ether, the ether extract was dried (anhydrous sodium sulfate), and concentrated under reduced pressure to give (4-Chloro-6-methoxy-1-tri-tert-butylsilanyl-1H-indol-3-ylmethyl)-dimethylamine as an oil (0.217 g, 98.6%). 1H NMR (CDCl3) δ:1.12 (d, 18H, J=7.52 Hz), 1.66 (m, 3H), 2.30 (s, 6H), 3.75 (s, 2H), 3.80 (s, 3H), 6.78 (d, 1H, J=2.2 Hz), 6.88 (d, 1H, J=2.2 Hz), 7.02 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH3:30]>C(O)C.O.CCOC(C)=O>[NH2:30][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1ccc(Oc2cc(Cl)ncn2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: N
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ncn1

Procedure:
In a sealed tube under N2-atmosphere, N-(4-(4-chloropyrimidin-6-yl-oxy)-phenyl)-N′-(4-chloro-3-trifluoromethyl-phenyl)-urea (443 mg, 1.00 mmol) and 25% aqueous NH3 (2 ml) in ethanol (2 ml) is stirred for 22 h at 80° C. Then the reaction mixture is diluted with water and AcOEt, the aqueous layer separated off and extracted 3 times with AcOEt. The organic phases are washed with 3 portions of water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; CH2Cl2/MeOH 9:1) yields the title compound: m.p.: 197-198° C.; 1H-NMR (DMSO6): 9.20 (s, HN), 8.93 (s, HN), 8.12 (m, 1H), 8.08 (s, 1H), 7.63 (m, 2H), 7.51 (d, 2H), 7.08 (d, 2H), 6.82 (s, H2N), 5.67 (s, 1H).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C:5]([N:7]1[CH2:28][CH2:27][C:10]2[C:11]3[C:16]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=4)=[N:15][CH:14]=[N:13][C:12]=3[S:26][C:9]=2[CH2:8]1)=[O:6].CCN(C(C)C)C(C)C.Cl.[O:39]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>CN(C=O)C>[Cl:25][C:20]1[CH:19]=[C:18]([NH:17][C:16]2[C:11]3[C:10]4[CH2:27][CH2:28][N:7]([C:5](=[O:6])/[CH:4]=[CH:3]/[CH2:2][N:42]5[CH2:43][CH2:44][CH2:45][O:39][CH2:40][CH2:41]5)[CH2:8][C:9]=4[S:26][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: C1CNCCOC1
Reactant: O=C(/C=C/CCl)N1CCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C/CN1CCCOCC1)N1CCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
To a solution of Example 59A (100 mg, 0.201 mmol) in DMF (2 mL) and DIPEA (0.10 mL, 0.60 mmol) was added 1,4-oxazepane hydrochloride (55 mg, 0.40 mmol). The mixture was stirred for 1 h at rt and then heated for 1 h to 50° C. The reaction mixture was directly separated by preparative HPLC. The product crystallized upon trituration with dichloromethane. The solvent was removed in vacuo to yield 83 mg (80%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[N+:16]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17]>C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:15][O:14][C:12]([C:4]1[CH:3]=[C:2]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:16]([O-:18])=[O:17])[CH:24]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[O:13]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: COC(=O)c1ccc(Br)cc1C(=O)OC
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccc(-c2cccc([N+](=O)[O-])c2)cc1C(=O)OC

Procedure:
n.m.r. δ values include 3.93 (s, 3 H), 3.94 (s, 3 H), 7.65 (t, 1 H), 7.78 (dd, 1 H), 7.86 (d, 1 H), 7.92-7.95 (m, 2 H), 8.26 (dd, 1 H), 8.46 (t, 1 H); from dimethyl 4-bromophthalate (1.80 g), tetrakis(triphenylphosphino)palladium(0) (246 mg) and 3-nitrophenylboronic acid (1.3 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][C:13]=3[C:12]([C:22]#[N:23])=[C:11]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].C1C[O:35]CC1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:35])[C:13]=3[C:12]([C:22]#[N:23])=[C:11]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cc(N3CCCCC3)c(C#N)c3c2-c2ccccc2C3)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2cc(N3CCCCC3)c(C#N)c3c2-c2ccccc2C3=O)cc1
Temperature: 2.5 °C

Procedure:
A solution of 4-(4-methoxyphenyl)-2-(piperidin-1-yl)-9H-fluorene-1-carbonitrile (380 mg) in THF was added sodium hydride (33 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Red solid; mp 210-212° C.;. FAB MS 395 (M+); IR (KBr) 2210 (CN), 1703 cm−1 (CO); HRMS calcd. for C26H22N2O2 394.1681 found 394, 1689.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:14][C:15]3[N:19]([CH3:20])[CH:18]=[N:17][CH:16]=3)[CH2:12][C@@H:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]([S:28]([CH2:31][CH2:32]N3CCOCC3)(=[O:30])=[O:29])[CH2:9][C:8]=2[CH:39]=1.CN1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.Cl.Cl.Cl.N1[CH:54]=[C:53](CN2C3C=CC(C4C=NC=CC=4)=CC=3CN(C(=O)C(F)(F)F)C(CC3C=CC=CC=3)C2)N=C1.CC(C)=O>CCCCCC>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:14][C:15]3[N:19]([CH3:20])[CH:18]=[N:17][CH:16]=3)[CH2:12][C@@H:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]([S:28]([CH2:31][CH2:32][C:53]3([CH3:54])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)(=[O:29])=[O:30])[CH2:9][C:8]=2[CH:39]=1
Reactant: Cn1cncc1CN1C[C@@H](Cc2ccccc2)N(S(=O)(=O)CCN2CCOCC2)Cc2cc(Cl)ccc21
Reactant: CN1CCNCC1
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Agent: Cl
Solvent: CCCCCC
Solvent: CC(C)=O
Product: Cn1cncc1CN1C[C@@H](Cc2ccccc2)N(S(=O)(=O)CCC2(C)CCNCC2)Cc2cc(Cl)ccc21
Yield: 28 %

Procedure:
Example 356 was prepared as a light yellow solid in 28% yield from Compound A of Example 353 and 1-methylpiperazine as described for Compound B of Example 353, with chromatography using 20% acetone in hexane followed by 10% methanol in CHCl3 and Compound C of Example 353, with purification by preparative HPLC only.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[C:11](=S)[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[CH2:8][C:6]=2[N:7]=1.O=C1C2C(=CC=CC=2)C(=O)[N:24]1[O:33][CH2:34][CH2:35][C@H:36]([O:41][CH3:42])[C:37]([O:39][CH3:40])=[O:38]>[Hg](OC(C)=O)OC(C)=O.C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2=[C:6]([CH2:8][C@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[NH:10]/[C:11]/2=[N:24]\[O:33][CH2:34][CH2:35][C@H:36]([O:41][CH3:42])[C:37]([O:39][CH3:40])=[O:38])[N:7]=1
Reactant: Cc1nc(N)nc2c1C(=S)N[C@@H](c1ccc(F)cc1Br)C2
Reactant: COC(=O)[C@H](CCON1C(=O)c2ccccc2C1=O)OC
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](CCO/N=C1\N[C@@H](c2ccc(F)cc2Br)Cc2nc(N)nc(C)c21)OC
Temperature: 100 °C
Yield: 11.6 %

Procedure:
A mixture of (R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione (31I, 146 mg, 0.4 mmol), (S)-methyl 4-(aminooxy)-2-methoxybutanoate (46c, 260 mg, 1.6 mmol), Hg(OAc)2 (257 mg, 0.8 mmol) and toluene (2 mL) was heated at 100° C. for 2 h. Cooled to rt, filtered through celite and purified to afford (S)-methyl 4-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-methoxybutanoate (23 mg, 12%) as off white solid. MS (ES) [M+H] calculated for C20H24BrFN5O4, 496.09. found 496.20.
Reaction SMILES: C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:15][O:16][C:17]1[CH:45]=[CH:44][C:20]([CH2:21][S:22][C@@H:23]2[CH2:27][N:26]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)=[O:29])[C@H:25]([C:41]([OH:43])=O)[CH2:24]2)=[CH:19][CH:18]=1.[C:46]([O:50][C:51]([N:53]1[CH2:58][CH2:57][NH:56][CH:55]([CH3:59])[CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]>C(#N)C.O1CCCC1>[CH3:15][O:16][C:17]1[CH:45]=[CH:44][C:20]([CH2:21][S:22][C@@H:23]2[CH2:27][N:26]([C:28]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=3)=[O:29])[C@H:25]([C:41]([N:56]3[CH2:57][CH2:58][N:53]([C:51]([O:50][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:52])[CH2:54][CH:55]3[CH3:59])=[O:43])[CH2:24]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: CC(C)(C)C(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(=O)OC(C)(C)C)CC3C)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reaction time: 0.33 h
Yield: 60.8 %

Procedure:
3.41 ml of triethylamine and 3.03 ml of pivaloyl chloride were added dropwise to a solution of 9.99 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid in 100 ml of dry acetonitrile, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 20 minutes. A solution of 5.38 g of 1-t-butoxycarbonyl-3-methylpiperazine in 50 ml of dry tetrahydrofuran was then added dropwise to the mixture, and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for 2 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed, in turn, with a 1N aqueous solution of oxalic acid, with water and with an aqueous solution of sodium chloride. The ethyl acetate solution was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and cyclohexane ranging from 1:1 to 3:2 by volume as the eluent, to give 8.56 g of the title compound, as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:30]([O:32]CC)=[O:31])[CH2:29][C:26]3([CH2:28][CH2:27]3)[CH2:25]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:30]([OH:32])=[O:31])[CH2:29][C:26]3([CH2:28][CH2:27]3)[CH2:25]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:11])[F:12]
Reactant: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CC2(CC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CC2(CC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
A mixture of ethyl 5-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-spiro[2,3]hexane-5-carboxylate (0.5 g, 0.9 mmol) and lithium hydroxide monohydrate (0.415 g, 9.88 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. Residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 5-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-spiro[2,3]hexane-5-carboxylic acid (0.29 g). 1H-NMR (CDCl3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.41 (s, 1H); 7.21 (s, 1H); 3.98 (q, 2H); 2.95 (d, 2H); 2.75 (d, 2H), 0.58 (t, 2H), 0.48 (t, 2H).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([OH:15])=O)[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[C:21]([F:30])[CH:20]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:26]#[N:27])([CH3:29])[CH3:28])=[C:21]([F:30])[CH:20]=3)=[O:15])[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Reactant: CC(C)(C#N)c1ccc(CN)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C#N)c1ccc(CNC(=O)Cn2cnc3cccc(C#N)c32)cc1F

Procedure:
2-(7-cyano-1H-benzimidazol-1-yl)-N-[4-(1-cyano-1-methylethyl)-3-fluorobenzyl]acetamide is synthesized according to example 14 with (7-cyano-1H-benzimidazol-1-yl)acetic acid (150 mg, 0.746 mmol) prepared according to scheme 3, 2-[4-(aminomethyl)-2-fluorophenyl]-2-methylpropanenitrile hydrochloride (205 mg, 0.896 mmol) prepared according to scheme 8, Et3N (250 μL, 1.79 mmol) and HATU (341 mg, 0.896 mmol) in DMF (3.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (50 21.2×50 mm, Mobile phase: A=water (0.075% TFA) B=MeCN (0.075% TFA). Yield=21 mg as TFA salt, 0.043 mmol, 6%); 1H NMR (400 MHz, DMSO-D6) δ ppm 1.62-1.71 (m, 6H), 4.32 (d, J=5.86 Hz, 2H), 5.26 (s, 2H), 7.13-7.25 (m, 2H), 7.29-7.41 (m, 2H), 7.71 (d, J=7.42 Hz, 1H), 8.00 (d, J=8.01 Hz, 1H), 8.36 (s, 1H), 8.84-8.93 (m, 1H). MS [M+H], calcd: 376.2. found: 376.0.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][OH:29])=[CH:23][CH:22]=1)[NH2:20]>>[C:1]1([C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][OH:29])=[CH:25][CH:26]=3)[N:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Reactant: NNc1ccc(CCO)cc1
Agent: Cl
Product: OCCc1ccc(-n2nc(-c3ccccc3)cc2-c2ccccc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from 1,3-diphenylpropane-1,3-dione and 2-(4-hydrazinophenyl)ethanol hydrochloride: MS (ESI) m/z 341 [M+H]+, 1H-NMR (CDCl3) δ 7.93-7.91 (2H, m), 7.46-7.20 (12H, m), 6.82 (1H, s), 3.87 (2H, br), 2.89 (2H, t, J=6.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH:11][C:12](=[O:15])[CH2:13]Cl.[CH3:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:19](C(O)=O)[C:18]=1N.NC1C=CC=C(C)C=1>CN(C)C=O>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH:11][C:12](=[O:15])[CH2:13][C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([CH3:16])[CH:18]=1
Reactant: Cc1cccc(C(=O)O)c1NC(=O)CCl
Reactant: Cc1cccc(C(=O)O)c1N
Solvent: Cc1cccc(N)c1
Solvent: CN(C)C=O
Product: Cc1cccc(CC(=O)Nc2c(C)cccc2C(=O)O)c1
Temperature: 90 °C
Yield: 49 %

Procedure:
3-Methyl-N(chloroacetyl)anthranilic acid 7.5 g (33 mmol)(synthesized from 3-methylanthranilic acid by the same procedures as those of Example 9) and m-toluidine 11 ml (0.10 mol) were dissolved in 60 ml of dimethylformamide and heated at 90° C. for 4 hours. The reaction solution was poured into ice water and extracted with ether. The resulting ether solution was extracted with 10% sodium hydroxide and the resluting aqueous solution was neutralized with 10% HCl solution. The neutralized solution was extracted with ether, and the ether solution was washed with water and dried. The solvent was distilled off and the residue was recrystallized from benzene-toluene to obtain 3-methyl-N[(3-methylphenyl)acetyl]anthranilic acid 4.8 g (yield: 49%).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[NH:8][C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].C1C(=O)N([Cl:22])C(=O)C1.CO>CN(C=O)C>[Cl:22][C:5]1[N:4]([CH2:1][CH:2]=[CH2:3])[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[NH:8][C:7]=2[N:6]=1
Reactant: C=CCn1cnc2[nH]c(=O)[nH]c(=O)c21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CO
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Temperature: 20 °C
Reaction time: 6 h
Yield: 62 %

Procedure:
To a solution of 7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione) (10.52 g, 54.7 mmol) in anhydrous DMF (60 ml) was added NCS (8.04 g, 60.2 mmol). The reaction mixture was left to stir under nitrogen at 20° C. for 6 hours. The reaction mixture was concentrated in vacuo to give an amber oil. MeOH was added and left to stand for 18 hours. The resulting residue was filtered and dried under vacuum to give the title compound (7.69 g, 62%). m/z 227.2[MH+].