Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[CH2:19]([O:26][C:27]1[N:31]([CH3:32])[N:30]=[C:29]([C:33](O)=[O:34])[CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.O>[CH2:19]([O:26][C:27]1[N:31]([CH3:32])[N:30]=[C:29]([C:33]([N:16]2[CH2:17][CH2:18][N:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:3]([CH3:6])([CH3:4])[CH3:5])[CH2:14][CH2:15]2)=[O:34])[CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: Cn1nc(C(=O)O)cc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1nc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (1.0 g, 3.4 mmol), 5-(benzyloxy)-1-methyl-1H-pyrazole-3-carboxylic acid (0.975 g, 4.2 mmol), triethylamine (1.39 mL, 10.0 mmol), EDCI (0.978 g, 5.1 mmol) and HOBt (0.781 g, 5.1 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to purify the residue by NH-silica gel column chromatography (hexane/ethyl acetate 90:10 to 0:100). Solvent was removed to obtain a solid (1.75 g, quant.).
Reaction SMILES: Br[CH2:2][CH:3]([CH3:7])[CH2:4][O:5][CH3:6].[Mg].[N:9]1[CH2:10][CH2:11][CH2:12][N:13]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15](=[O:22])[C:14]=12.[Cl-].[NH4+]>CCOCC.ClCCCl>[OH:22][C:15]1([CH2:2][CH:3]([CH3:7])[CH2:4][O:5][CH3:6])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[N:13]2[CH2:12][CH2:11][CH2:10][N:9]=[C:14]12
Reactant: COCC(C)CBr
Reactant: O=C1C2=NCCCN2c2ccccc21
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: ClCCCl
Product: COCC(C)CC1(O)C2=NCCCN2c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-Bromo-3-methoxy-2-methylpropane (10.02 g) in ether (50 ml) was added dropwise over 20 minutes to magnesium turnings (1.46 g) in ether (10 ml). The mixture was stirred under argon at room temperature for 30 minutes, cooled to 0° and 3,4-dihydropyrimido[1,2-a]indol-10(2H)-one (3.72 g) in dry 1,2-dichloroethane (20 ml) added dropwise over 20 minutes. The solution was stirred under argon at 0° for 1 hour, poured onto a swirling mixture of ice (100 ml) and saturated aqueous ammonium chloride (60 ml). The mixture was stirred for 20 minutes and concentrated in vacuo. The aqueous residue was extracted with chloroform (3×100 ml). The extracts were dried (Na2SO4) and concentrated in vacuo. Ether (20 ml) was added and the product was filtered and recrystallised from ethyl acetate to give the title compound as the free base (2.85 g), m.p. 162°-167° C. The free base was acidified with ethereal HCl to give the title compound as the hydrochloride, m.p. 244° (dec.).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:49][O:50][CH3:51])[C:8]([NH:10][CH:11]2[C:18](=[O:19])[N:17]3[CH:12]2[S:13][CH2:14][C:15]([CH:36]=[CH:37][O:38][S:39]([C:42]2[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=2)(=[O:41])=[O:40])=[C:16]3[C:20]([O:22]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:21])=[O:9])[N:6]=1.C(O)=O>O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:49][O:50][CH3:51])[C:8]([NH:10][CH:11]2[C:18](=[O:19])[N:17]3[CH:12]2[S:13][CH2:14][C:15]([CH:36]=[CH:37][O:38][S:39]([C:42]2[CH:43]=[CH:44][C:45]([CH3:46])=[CH:47][CH:48]=2)(=[O:40])=[O:41])=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=COS(=O)(=O)c3ccc(C)cc3)CSC12)c1csc(N)n1
Solvent: O
Solvent: O=CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=COS(=O)(=O)c3ccc(C)cc3)CSC12)c1csc(N)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
A mixture of 7-[2-(2-amino-thiazol-4-yl)-2-methoxyimino-acetamido]-2-benzhydryloxycarbonyl-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (syn isomer, E-form) (0.35 g), formic acid (10 cc) and water (3 cc) is stirred at 50° C. for 30 minutes. Water (8 cc) is then added, and the mixture is filtered and concentrated to dryness at 30° C. under 0.05 mm Hg (0.007 kPa). The residue is taken up in ethanol (2×20 cc), and in each case the mixture is concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa). The solid obtained is triturated in diethyl ether (20 cc). After filtration and drying, 7-[2-(2-amino-thiazol-4-yl)-2-methoxyimino-acetamido]-2-carboxy-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (syn isomer, E-form) (0.12 g) is obtained in the form of a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4][NH2:5].C(N(CC)C(C)C)(C)C.[Br:23][C:24]1[CH:25]=[N:26][C:27](Cl)=[N:28][CH:29]=1>O1CCOCC1>[Br:23][C:24]1[CH:25]=[N:26][C:27]([NH:5][CH2:4][C:3]2[CH:6]=[C:7]([C:10]([F:11])([F:12])[F:13])[CH:8]=[CH:9][C:2]=2[F:1])=[N:28][CH:29]=1
Reactant: NCc1cc(C(F)(F)F)ccc1F
Reactant: Clc1ncc(Br)cn1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(C(F)(F)F)cc1CNc1ncc(Br)cn1
Temperature: 25 °C
Yield: 46.6 %

Procedure:
2-Fluoro-5-trifluoromethyl-benzylamine (2.0 g) is dissolved in 1,4-dioxane (10 ml) and thereto are added N,N-diisopropylethylamine (2.7 ml) and 5-bromo-2-chloropyrimidine (3.02 g) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3) to give (5-bromo-pyrimidin-2-yl)-(2-fluoro-5-trifluoromethyl-benzyl)-amine (1.69 g). MS (m/z): 350/352 [M+H]+
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]([C:9]2[CH:14]=[CH:13][C:12](OC)=[CH:11][CH:10]=2)=[C:7]([NH2:17])[NH:6][N:5]=1.[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([CH2:26][C:27](=O)[C:28](OC)=[O:29])[CH:23]=[CH:24][CH:25]=1.[C:35](OCC)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]1[C:8]([C:9]2[CH:10]=[CH:11][C:12]([CH3:35])=[CH:13][CH:14]=2)=[C:7]2[NH:17][C:28](=[O:29])[CH:27]=[C:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:33])([F:34])[F:18])[CH:21]=3)[N:6]2[N:5]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)C(=O)Cc1cccc(C(F)(F)F)c1
Reactant: COCc1n[nH]c(N)c1-c1ccc(OC)cc1
Solvent: c1ccncc1
Product: COCc1nn2c(-c3cccc(C(F)(F)F)c3)cc(=O)[nH]c2c1-c1ccc(C)cc1
Temperature: 95 °C
Reaction time: 12 h

Procedure:
3-(Methoxymethyl)-4-(4-methoxyphenyl)-1H-pyrazol-5-amine (1.4 g, 6.0 mmol) and methyl 3-(trifluoromethyl)phenyloxopropanoate (2.2 g, 1.5 eq) are dissolved in pyridine (10 mL) and stirred at 95° C. for 12 hours under reflux. Upon completion of the reaction, 2.1 g of the target compound is obtained by purification by column chromatography (ethyl acetate 100%).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:21]=[C:20]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(-c2cccc(F)c2)c(-c2ccccc2)n1
Yield: 61.5 %

Procedure:
6-(3-Fluorophenyl)-5-phenyl-1,2,4-triazin-3-amine (49 mg, 62%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3-fluorophenylboronic acid (48.1 mg, 0.344 mmol) according to the general procedure of Example 1.
Reaction SMILES: Cl/[CH:2]=[CH:3]\[C:4]#[C:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12]>[Pd]>[CH3:10][Si:11]([CH3:13])([CH3:12])[C:14]#[C:15][CH:2]=[CH:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC#C/C=C\Cl
Reactant: C#C[Si](C)(C)C
Agent: [Pd]
Product: CCCCC#CC=CC#C[Si](C)(C)C
Yield: 53 %

Procedure:
According to Method A of the above-described General Synthesis Procedures I, the coupling reaction of compound (a4) from Example 4 with trimethylsilylacetylene using palladium as a catalyst gave the title compound (a5) as an oil in 53% yield.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][CH:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH:18]([CH3:20])[CH3:19])[C:3]1=[O:21].C(N(CC)CC)C.Cl[C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:38]=2)[N:33]=[CH:32][N:31]=1>CCO>[CH:18]([C@@H:8]1[CH2:9][C@H:10]([N:13]([CH:15]([CH3:16])[CH3:17])[CH3:14])[CH2:11][CH2:12][C@@H:7]1[N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:42])([F:43])[F:41])[CH:38]=3)[N:33]=[CH:32][N:31]=2)[C:3]1=[O:21])([CH3:20])[CH3:19].[CH:18]([C@@H:8]1[CH2:9][C@@H:10]([N:13]([CH:15]([CH3:16])[CH3:17])[CH3:14])[CH2:11][CH2:12][C@@H:7]1[N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:42])([F:43])[F:41])[CH:38]=3)[N:33]=[CH:32][N:31]=2)[C:3]1=[O:21])([CH3:20])[CH3:19]
Reactant: CC(C)[C@@H]1CC(N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)[C@@H]1C[C@@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Product: CC(C)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 80 °C

Procedure:
To a solution of (S)-3-amino-1-((1S,2S,4R/S)-2-isopropyl-4-(isopropyl(methyl)amino)cyclohexyl)pyrrolidin-2-one (85 mg) in EtOH (2.5 mL) was added triethylamine (0.2 mL) and 4-chloro-6-(trifluoromethyl)quinazoline (100.1 mg). The mixture was heated at 80° C. for 14 h before it was filtered and concentrated in vacuo. The residue was purified by chiral chromatography (AD column, EtOH as mobile phase) to afford (S)-1-((1S,2S,4R)-2-isopropyl-4-(isopropyl(methyl)amino)cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one [52 mg; MS found: (M+H)+=492.4] and (S)-1-((1S,2S,4S)-2-isopropyl-4-(isopropyl(methyl)amino)cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one [8 mg; MS found: (M+H)+=492.4].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[NH:27][N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1.[OH-].[K+].Cl[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([S:40][CH3:41])=[CH:36][CH:35]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([S:40][CH3:41])=[CH:36][CH:35]=4)[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:13]=2[C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[CH:4][CH:3]=1.[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[N:27]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([S:40][CH3:41])=[CH:36][CH:35]=4)[N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1
Reactant: CSc1ccc(CCl)cc1
Reactant: Fc1ccc(-c2nc3[nH]ncc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CSc1ccc(Cn2cc3c(-c4ccc(F)cc4)c(-c4ccncc4)c(-c4ccc(F)cc4)nc3n2)cc1
Product: CSc1ccc(Cn2ncc3c(-c4ccc(F)cc4)c(-c4ccncc4)c(-c4ccc(F)cc4)nc32)cc1
Temperature: 60 °C
Yield: 47 %
Yield: 25 %

Procedure:
In a volumetric flask, 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.30 g, 78.0 mmol, obtained in example 1) and DMF (3.5 mL) were introduced under argon atmosphere. KOH (0.06 g, 1.1 mmol) was added followed by a solution of 1-chloromethyl-4-(methylsulfanyl)benzene (0.15 g, 0.9 mmol, obtained in section a) in DMF (0.4 mL). This was heated to 60° C. overnight. It was allowed to cool and concentrated. The residue was dissolved in a mixture of water and EtOAc. The two phases were separated. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 0.10 g of 4,6-bis(4-fluorophenyl)-2-(4-methylsulfanylbenzyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (yield: 25%) and 0.19 g of 4,6-bis(4-fluorophenyl)-1-(4-methylsulfanylbenzyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (yield: 47%).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](Cl)(=[O:5])=[O:4].[Li+:9].[Li+].[Li+].[NH2-:12].CN(C=O)C>COCCOC>[N-:12]([S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4])[S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4].[Li+:9]
Reactant: [NH2-]
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Temperature: 25 °C

Procedure:
22 ml of trifluoromethanesulfonyl chloride were added to a suspension of 3.5 g of lithium nitride in 100 ml of a mixture of DMF and DME (50/50). The nitride dissolved in a few minutes with stirring at ambient temperature. The reaction took place according to the following reaction scheme:
Reaction SMILES: [C:1]([O-])(=[S:3])[CH3:2].[K+].Br[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:9]>C(O)C>[C:1]([CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:9])(=[S:3])[CH3:2]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCO
Product: COc1ccc(C(=O)CC(C)=S)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.6 %

Procedure:
Potassium thioacetate (2.28 g, 20 mmol) was added to a solution of 2-bromo-4′-methoxy acetophenone (4.58 g, 20 mmol) in absolute ethanol (150 ml). the reaction was stirred at ambient temperature under nitrogen for 16 hours at which time the white precipitate that had formed was filtered and the ethanol removed at reduced pressure. The residue was dissolved in dichloromethane (250 ml) and washed with water (200 ml), brine (200 ml), dried over Na2SO4 and the solvent removed at reduced pressure. The resulting residue was chromatographed on silica with a gradient from 10%-35% ethyl acetate in hexane to yield 3.4 g (76%) of 2-thioacetyl-4′-methoxy acetophenone. 1H NMR (CDCl3) δ 2.36 p (s, 3h), 3.84 (s, 3h), 4.33 (s, 2h), 6.9 (d, 2h, J=9.2 Hz), 7.9 (d, 2h, J=9.2 Hz).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][N:5]1[CH2:12][CH:11]2[CH:7]([CH2:8][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[S:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)=[CH:16][CH:15]=3)[CH2:10]2)[CH2:6]1.[OH-].[K+]>C(O)(C)C.O>[S:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:9]2[CH2:8][CH:7]3[CH2:6][N:5]([CH2:4][C:3]([OH:30])=[O:2])[CH2:12][CH:11]3[CH2:10]2)=[CH:19][CH:18]=1
Reactant: COC(=O)CN1CC2CN(Cc3ccc(Oc4nc5ccccc5s4)cc3)CC2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)CN1CC2CN(Cc3ccc(Oc4nc5ccccc5s4)cc3)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
A solution of {5-[4-(benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-acetic acid methyl ester (233 mg, 0.55 mmol) in 1:1 isopropanol/water (2 mL) was treated with KOH (62 mg, 1.1 mmol). The reaction stirred at rt overnight. The reaction was acidified to pH 6.5 and extracted with 25% isopropanol/CHCl3 to afford pure acid as a white powder (67 mg, 30%). MS (ESI): Mass calcd for C22H23N3O3S, 409.5; m/z found, 410.2 [M+H]+; 1H NMR (400 MHz, CD3OD): 7.78 (d, J=8.0 Hz, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.57 (d, J=8.6 Hz, 2H), 7.45-7.35 (m, 3H), 7.34-7.28 (m, 1H), 3.76 (s, 2H), 3.64 (s, 2H), 3.55-3.35 (m, 4H), 3.12-2.97 (m, 2H), 2.94 (d, J=9.9 Hz, 2H), 2.52-2.34 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:24])=[C:19]([CH:21]=[CH:22][CH:23]=2)[NH2:20])[CH:5]=[CH:4][N:3]=1.[CH3:25][Zn]C>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:25])[N:7]=2)=[C:9]([C:17]2[C:18]([F:24])=[C:19]([CH:21]=[CH:22][CH:23]=2)[NH2:20])[N:10]=1)([CH3:16])[CH3:15]
Reactant: C[Zn]C
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Product: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(N)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline (1.0 g, 2.76 mmol) and dimethylzinc (2.76 mL, 5.51 mmol), the title compound was obtained as an off white solid (0.8 g, 85% yield). MS (ESI): 343 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]([NH:17][NH2:18])=O)[O:12][N:11]=2)=[CH:6][CH:5]=1.Cl.[C:22](=N)([NH2:24])[CH3:23].[OH-].[Na+].CCOC(C)=O>C1COCC1>[CH3:23][C:22]1[NH:18][N:17]=[C:15]([C:13]2[O:12][N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:20])([F:19])[F:1])=[CH:5][CH:6]=3)[N:14]=2)[N:24]=1
Reactant: NNC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Reactant: CC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 45.8 %

Procedure:
To a solution of 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carbohydrazide (9.7 g, 33.7 mmol) and acetimidamide hydrochloride (4.8 g, 50.5 mmol) in dry THF (300 mL), NaOH (2.0 g, 50.5 mmol) was added at RT. The mixture was refluxed overnight. The solution was cooled, concentrated and ethane-1,2-diol (100 mL) was added. The resulting mixture was heated at 180° C. for 3 h, cooled to RT, diluted with H2O (800 mL), and extracted with EtOAc (3×400 mL). The combined organic layers were washed with H2O (300 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the crude solid product, which was treated with EtOAc (150 mL). The resulting suspension was stirred at RT for 15 min, and then filtered to afford 4.8 g of the pure desired compound. The remaining filtrate was concentrated and purified by silica gel column chromatography (Petroleum ether:EtOAc=1:1) to afford 1.4 g of another batch of 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a white solid-overall 6.2 g, yield 59%. MS (ES+) C12H8F3N5O2 requires: 311. found: 312 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([CH:15]2[CH2:17][CH:16]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.[F:24][C@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>CN1C(=O)CCC1.CS(C)=O.CO>[F:24][C@H:25]1[CH2:29][CH2:28][N:27]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13]([CH:15]3[CH2:17][CH:16]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:14])[CH:3]=2)[CH2:26]1
Reactant: F[C@H]1CCNC1
Reactant: Cc1cc2nc(NC(=O)C3CC3c3ccccc3)cc(Cl)n2n1
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Product: Cc1cc2nc(NC(=O)C3CC3c3ccccc3)cc(N3CC[C@H](F)C3)n2n1
Temperature: 25 °C
Yield: 9.2 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-phenylcyclopropanecarboxamide (8C, 200 mg, 1.69 mmol) and (S)-3-fluoropyrrolidine (302 mg, 3.38 mmol) in NMP (5 mL) was stirred at 100° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (35-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (59 mg, 44%). 1H NMR (DMSO-d6) δ: 10.87 (s, 1H), 7.26-7.35 (m, 2H), 7.13-7.24 (m, 3H), 6.83 (s, 1H), 5.99 (s, 1H), 5.29-5.58 (m, 1H), 3.72-4.50 (m, 4H), 2.40-2.47 (m, 1H), 2.22-2.36 (m, 5H), 2.15 (br. s., 1H), 1.50 (dt, J=9.2, 4.6 Hz, 1H), 1.35-1.44 (m, 1H). ESI-MS: m/z 380.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])[CH3:2].C(N(CC)CC)C.[NH2:20][C:21]1[CH:42]=[CH:41][C:24]([C:25]([N:27]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[CH2:31][N:30]3[CH:38]=[CH:39][CH:40]=[C:29]3[CH2:28]2)=[O:26])=[CH:23][CH:22]=1>C(Cl)Cl>[CH:40]1[CH:39]=[CH:38][N:30]2[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N:27]([C:25]([C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:6](=[O:7])[C:5]4[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=4[O:3][CH2:1][CH3:2])=[CH:42][CH:41]=3)=[O:26])[CH2:28][C:29]=12
Reactant: CCOc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 0.05 h
Yield: 119.6 %

Procedure:
To a stirred solution of 0.362 g of 2-ethoxybenzoyl chloride 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 72 hours at room temperature. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give 0.890 g of solid which is crystallized from ethyl acetate to give 0.540 g of the desired product as a white solid, m.p. 160°-176° C.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[N+]([C:24]1[O:28][C:27]([CH:29]=[O:30])=[CH:26][CH:25]=1)([O-])=O.O>O1CCCC1>[C:15]([Si:12]([CH3:13])([CH3:14])[O:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][C:24]3[O:28][C:27]([CH:29]=[O:30])=[CH:26][CH:25]=3)=[N:3][C:4]=2[CH:10]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2nc(S)[nH]c2c1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c(Sc3ccc(C=O)o3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
Aldehyde intermediate preparation: A solution of 2-mercapto-5-(tert-butyl-dimethyl-silanyloxy)-benzimidazole (2.07 g, 7.38 mmol) in tetrahydrofuran (15 ml) is added dropwise to a mixture of sodium hydride (60% dispersion in mineral oil, 0.472 g, 11.8 mmol) and tetrahydrofuran (5 ml) at 0° C. The mixture is stirred at room temperature for 3 hours. A solution of 5-nitro-2-furaldehyde (1.04 g, 7.38 mmol) in tetrahydrofuran (10 ml) is then added dropwise over a 15 minute period and the mixture is stirred for 16 hours at room temperature. Water (10 ml) is then added and the reaction mixture is concentrated under reduced pressure. The residue is dissolved in a minimal volume of ethyl acetate and is filtered through a silica gel plug (20 ml) that is eluted with 500 ml of ethyl acetate. The organic filtrates are concentrated under reduced pressure and are purified on a silicagel column (120 g) eluted with a mixture of cyclohexane and ethyl acetate (7/3, v/v) to yield 1.4 g of 5-[5-(tert-butyl-dimethyl-silanyloxy)-1H-benzimidazol-2-ylsulfanyl]-furan-2-carbaldehyde as a brown oil. Yield=51%. Analytical LC/MS (method B): retention time=4.62 min., m/z=375.05 (positive ion mode).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH3:13][C:14]1[N:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:20][C:18]1[CH:17]=[CH:16][C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:14]([CH3:13])[N:19]=1)=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1ccccc1Br
Reactant: Cc1nc(N)ccc1-c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc(NC(=O)NC(=O)c2ccccc2Br)ccc1-c1ccccc1

Procedure:
2-Bromobenzoyl isocyanate (650 mg) is reacted with 6-methyl-5-phenyl-2-pyridylamine (500 mg) in 25 ml of ethyl acetate. A precipitate forms which upon filtering constitutes the desired product.