Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[CH:21]4)[CH2:16][CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C(OC([NH:41][CH2:42][CH2:43][C:44](N(OC)C)=[O:45])=O)(C)(C)C>C1COCC1>[NH2:41][CH2:42][CH2:43][C:44]([C:21]1[N:20]([CH:17]2[CH2:16][CH2:15][N:14]([C:7]3([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]3)[CH2:19][CH2:18]2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=1)=[O:45]
Reactant: CON(C)C(=O)CCNC(=O)OC(C)(C)C
Reactant: c1ccc(C2(N3CCC(n4cnc5ccccc54)CC3)CCCCCC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: NCCC(=O)c1nc2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a stirred solution of 1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazole (Example 12, 66.3 mg, 0.178 mmol) in THF(4 ml) was added n-butyllithium (1.54M solution in hexane, 0.923 ml, 1.42 mmol) at −78° C. After 1 h stirring at −78° C., a solution of 3-t-butoxycarbonylamino-N-methoxy-N-methylpropionamide (140 mg, 0.604 mmol, this was prepared according to the reported procedure: G. Bitan et al, J. Chem. Soc., Perkin Trans. 1, 1997, 1501-1510) in THF (1.5 ml) was added to the reaction mixture at −78° C. After 0.5 h stirring at −78° C. and 15 h stirring at ambient temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The extracts combined were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by preparative TLC (1 mm plate×3, n-hexane/acetone: 5/1, 6 times developed) to give 71.7 mg (74%) of pale brown amorphous solid. This solid (70 mg, 0.131 mmol) was dissolved in HCl solution in MeOH (10 ml). After evaporation of the solvent, the residue was dried in vacuo at 45° C. for 18 h to afford 60 mg (89%) of pale brown amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]4[CH:19]=[CH:20][C:21]([C:23](O)=[O:24])=[CH:22][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:23]([C:21]2[CH:20]=[CH:19][C:13]3[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:27]=[CH:26][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:22]=2)=[O:24])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Yield: 61.2 %

Procedure:
4-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (160 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylic acid (180 mg), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (150 mg), HBTU (200 mg), and DIEA (1.2 mL) in DMF (2 mL).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([OH:17])[CH2:11][C:12](OCC)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C(O)C>[CH2:1]([O:8][CH2:9][C@@H:10]([OH:17])[CH2:11][C:12]([NH:19][NH2:20])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C[C@H](O)COCc1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)C[C@H](O)COCc1ccccc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
In a 100 ml flask were put 4.15 g (17.4 mmol) of ethyl (S)-4-benzyloxy-3-hydroxybutyrate (optical purity: 89%e.e.) prepared in Reference Example 2, 20 ml of ethanol, and 2.62 g (52.2 mmol) of hydrazine monohydrate in a nitrogen stream, and the mixture was heated under reflux for 20 hours. The reaction mixture was cooled to room temperature (22 to 24° C.), and ethanol was removed by evaporation under reduced pressure. To the residue was added 40 ml of diethyl ether, followed by heating under reflux to dissolve the crude crystals. The solution was cooled to 5° C., followed by stirring for 1 hour. The crystals thus precipitated were collected by filtration and washed with 10 ml of diethyl ether to give 2.90 g (74%) of the title compound. Melting point: 96.9° C. Optical purity: >99.9%e.e.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:12][C:11]2([CH2:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:27][O:28]C4CCCCO4)=[O:26])[CH:18]=3)[O:13]2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CCOCC.C(Cl)Cl>[CH2:2]([N:9]1[CH2:10][C:11]2([CH2:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:27][OH:28])=[O:26])[CH:18]=3)[O:13]2)[CH2:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccccc3)C1)O2)NOC1CCCCO1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccccc3)C1)O2)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
1 M HCl in Et2O (5.0 ml) was added dropwise to a solution of (E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (360 g, 0.80 mmol) in DCM (4 ml). The mixture was stirred at RT overnight. The formed precipitate was filtered off, washed with DCM, dried under vacuum and purified by preparative HPLC to give (E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide (290 mg, trifluoroacetate salt) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:7](O)=[N:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:7]1[C:6]([C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1
Reactant: O=[N+]([O-])c1cnc(O)c(C(F)(F)F)c1
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1

Procedure:
Heat a mixture of 5-nitro-3-trifluoromethyl-pyridin-2-ol (416 mg, 2.0 mmol) and phosphorus oxychloride (1 mL) at 85° C. for 18 hours. Cool the mixture and remove the volatiles by rotary evaporation. Dissolve the residue in EtOAc (15 mL) and wash with water (10 mL), saturated NaHCO3(aq) (10 mL) and brine (10 mL). Dry the organic extract over MgSO4 and remove the solvent under reduced pressure to yield the title compound.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[S:22][CH:21]3[CH:23]=[C:24]([Br:26])[S:25][CH:20]3[CH:19]=2)=[CH:16][N:17]=1)=[O:7])(C)(C)C.Cl.[CH3:28][O:29][C:30]([NH:32][CH:33]([CH:37]([CH3:39])[CH3:38])C(O)=O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.CN(C=O)C>[CH3:28][O:29][C:30](=[O:31])[NH:32][CH:33]([C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[S:22][CH:21]3[CH:23]=[C:24]([Br:26])[S:25][CH:20]3[CH:19]=2)=[CH:16][N:17]=1)=[O:7])[CH:37]([CH3:39])[CH3:38]
Reactant: COC(=O)NC(C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(C2=CC3SC(Br)=CC3S2)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(C2=CC3SC(Br)=CC3S2)[nH]1)C(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.6 %

Procedure:
2-[5-(5-Bromo-3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (250 mg, 0.548 mmol) was dissolved in DCM (4 mL) and treated with HCl (4 M in dioxane, 1 mL, 4 mmol). After stirring for 1.5 h, the reaction mixture was concentrated. The solid was dried, then combined with 2-Methoxycarbonylamino-3-methyl-butyric acid (106 mg, 0.603 mmol), HATU (229 mg, 0.603 mmol) and DMF (6 mL). The stirred reaction mixture was cooled to 0° C. and DIPEA (0.48 mL, 2.74 mmol) was added dropwise. After 50 min, it was warmed to RT. 12 min later, the reaction mixture was diluted with EtOAc. The organic phase was washed with saturated aqueous NaHCO3 and brine before being dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography to afford the title compound (252 mg, 90%).
Reaction SMILES: [Na].[OH:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)S(O)(=O)=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[C-:30]#[N:31].[Na+]>O>[C:30]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)[OH:2])#[N:31]
Reactant: O=S(=O)(O)C(O)c1cccc(Oc2ccccc2)c1
Reactant: [C-]#N
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: N#CC(O)c1cccc(Oc2ccccc2)c1
Temperature: 15 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Into a flask were placed 755.7 g (2.5 moles) of the sodium salt of (hydroxy)(3-phenoxyphenyl)methanesulfonic acid, 237.6 g (1.25 moles) of sodium metabisulfite, and 2273 ml of water. The flask was cooled to 15° C. and a solution of 245.1 g (5.0 moles) of sodium cyanide in 302 ml of water was added dropwise. The reaction mixture was allowed to warm to room temperature, was stirred for 3 hours, then extracted three times with 800 ml of diethyl ether. The extract was washed once with 800 ml of a solution of 25% sodium metabisulfite and 1 N hydrochloric acid and twice with distilled water. After being dried over magnesium sulfate, the ether was evaporated, leaving a residue of 498.5 g of 94% (cyano)(3-phenoxyphenyl)methanol by gc analysis.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1.[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(CN(C(=O)OC(C)(C)C)n2cccc2)cc1

Procedure:
Prepared according to the benzylation condition used in Example 1 step b) from pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 4-methoxybenzyl chloride (1.03 eq.) and sodium hydride (1.3 eq.). ESI (m/z): 303 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH:3]=O.O.[C:9]([C:13]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[CH:15][C:14]=1[OH:23])([CH3:12])([CH3:11])[CH3:10].CNC>CO>[C:9]([C:13]1[C:14]([OH:23])=[C:15]([CH2:3][C:2]([CH3:1])([CH3:7])[CH:5]=[O:6])[CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C=O)CO
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: CNC
Solvent: CO
Solvent: O
Product: CC(C)(C=O)Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Reaction time: 20 h
Yield: 61 %

Procedure:
125 g (1 mol) of 80% strength aqueous 2,2-dimethyl-3-hydroxypropanal (crude mixture from the synthesis, reduced to a water content of 20% by distillation), 185 g (0.9 mol) of 2,4-di-t-butylphenol, 24 g (0.22 mol) of 40% strength aqueous dimethylamine and 700 g of methanol are reacted in a stirred autoclave under autogenous pressure of 20-30 bar at 160° C. for 20 h and then at 180° C. for 20 h. Workup of the reaction mixture by distillation yields 159 g (61%) of 3-(3,5-di-t-butyl-2-hydroxyphenyl)-2,2-dimethylpropanal (boiling point 115°-116° C.).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]3[C:17]([CH2:20]Cl)=[N:18][N:19]=[C:15]3[CH2:14][N:13]=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:11]=2[CH:28]=1.[I-].[Na+]>CN(C)C=O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]3[C:17]([CH2:20][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[N:18][N:19]=[C:15]3[CH2:14][N:13]=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:11]=2[CH:28]=1
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Reactant: CCNCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 1 ml. of diethylamine in 5 ml. of dry dimethylformamide, 350 mg. of 8-bromo-1-(chloromethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine (obtained as in Preparation 3) is added and the mixture stirred under nitrogen at room temperature for about 4.5 hours. To the mixture, 50 mg. of sodium iodide is added and stirring is continued at room temperature for about 18 hours and then heated at about 100 to about 110° C. for about an additional 6 hours. It is then poured into ice water and extracted with chloroform. The extract is washed with water, dried over anhydrous potasssium carbonate and concentrated under vacuum. The residue is crystallized from ethyl acetate: Skellysolve B to give pure 8-bromo-1-[(diethylamino)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine (I).
Reaction SMILES: [Na].[CH:2]1([C:5](=[N:7][OH:8])[NH2:6])[CH2:4][CH2:3]1.[CH3:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]2[CH:20]=[N:21][C:22]([C:23](OCC)=O)=[C:12]2[C:11]1=[O:28]>C(O)C>[CH:2]1([C:5]2[N:6]=[C:23]([C:22]3[N:21]=[CH:20][N:13]4[C:14]5[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=5)[N:10]([CH3:9])[C:11](=[O:28])[C:12]=34)[O:8][N:7]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ncn2c1c(=O)n(C)c1ccccc12
Reactant: NC(=NO)C1CC1
Agent: [Na]
Solvent: CCO
Product: Cn1c(=O)c2c(-c3nc(C4CC4)no3)ncn2c2ccccc21

Procedure:
50 mg of sodium was dissolved in 25 ml of dry ethanol containing 3 g of molecular sieves (4 Å) and 0.5 g of cyclopropylcarboxamide oxime was added to this mixture and thereupon 0.6 g of ethyl 4,5-dihydro-5-methyl-4-oxo-imidazo(1,5-a)quinoxaline-3-carboxylate. The resulting mixture was refluxed for 2 hours, whereafter the molecular sieves were filtered off. The title compound was isolated after evaporation of the solvent in vacuo, followed by addition of icewater and filtration. yield 0.4 g of title compound. M.p. 224.7°-225.6° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][N:6]=[CH:5][N:4]=1.[CH3:14][O:15][C:16](=[O:41])[C@H:17]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1)[NH:18][C:19]([C:21]1([CH2:25][CH2:26][CH2:27][CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH2:24][CH2:23][CH2:22]1)=[S:20].COC(=O)[C@H](CC1C=CC(NC(C2C=NC(C(F)(F)F)=NC=2)=O)=CC=1)NC(C1(CCCCS(C)(=O)=O)CCC1)=S>>[CH3:14][O:15][C:16](=[O:41])[C@H:17]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:9]([C:8]2[C:3]([C:2]([F:1])([F:13])[F:12])=[N:4][CH:5]=[N:6][CH:7]=2)=[O:11])=[CH:36][CH:35]=1)[NH:18][C:19]([C:21]1([CH2:25][CH2:26][CH2:27][CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH2:22][CH2:23][CH2:24]1)=[S:20]
Reactant: O=C(O)c1cncnc1C(F)(F)F
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCC1
Agent: COC(=O)[C@H](Cc1ccc(NC(=O)c2cnc(C(F)(F)F)nc2)cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCC1
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2cncnc2C(F)(F)F)cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCC1
Yield: 32 %

Procedure:
Using the general procedure described in example 45, starting with 4-(trifluoromethyl)pyrimidine-5-carboxylic acid and 4-amino-N-[[1-[4-(methylsulfonyl)butyl]cyclobutyl]thioxomethyl)-L-phenylalanine methyl ester, N-[[1-[4-(methylsulfonyl)butyl]cyclobutyl]thioxomethyl]-4-[[[2-(trifluoromethyl) pyrimidin-5-yl]carbonyl]amino]-L-phenylalanine methyl ester was prepared in 32% yield as an amorphous colorless solid. HR MS: Obs. mass, 601.1766. Calcd. mass, 601.1766 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].[NH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=[O:24]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C(CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)N1CCCCC1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and piperidine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[CH:13][C:14]([F:25])=[C:15]([C:17]4[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:16]=3)=[CH:9][N:10]=[C:4]2[N:3]=1.[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1>>[F:25][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([C:28]4[CH:29]=[CH:30][S:26][CH:27]=4)=[N:3][C:4]3=[N:10][CH:9]=2)=[CH:16][C:15]=1[C:17]1[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OB(O)c1ccsc1
Reactant: N#Cc1ccccc1-c1cc(-c2cnc3nc(Cl)ccn23)ccc1F
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(-c4ccsc4)ccn23)ccc1F
Yield: 77.6 %

Procedure:
5′-(7-Chloroimidazo[1,2-α]pyrimidin-3-yl)-2′-fluorobiphenyl-2-carbonitrile (50 mg, 0.143 mmol) and 3-thiopheneboronic acid (346 mg, 0.287 mmol) were reacted using the procedure in Example 23 to give 2′-fluoro-5′-[7-(thien-3-yl)imidazo[1,2-α]pyrimidin-3-yl]biphenyl-2-carbonitrile (44 mg, 77%) as a yellow powder: δH (400 MHz, CDCl3) 7.31 (1H, d, J 7), 7.39-7.45 (2H, m), 7.55 (1H, dt, J 9 and 1), 7.61-7.67 (3, m), 7.71 (1H, dt, J 8 and 1), 7.84-7.90 (3H, m), 8.11 (1H, s), 8.82 (1H, d, J 7); m/z (ES+) 397 (M++H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[CH3:23])=[CH:20][C:19]([C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[CH:18][CH:17]=2>>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=1)[CH2:2][N:15]1[C:16]2[C:21](=[CH:20][C:19]([C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[CH:18][CH:17]=2)[C:22]([CH3:23])=[C:14]1[CH3:13])=[O:7]
Reactant: C=CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Reactant: COC(=O)c1cccc(CBr)c1
Product: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1cccc(C(=O)OC)c1

Procedure:
The title compound was prepared following the same general protocol as described in Step 2, Example 1, using methyl 3-(bromomethyl)benzoate and allyl 2,3-dimethyl-1H-indole-5-carboxylate.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1.C(N(C(C)C)CC)(C)C>C(O)C>[F:28][C:26]([F:27])([F:29])[C:23]1[N:21]2[N:22]=[C:17]([N:7]3[CH2:6][CH:5]4[CH2:1][N:2]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH:4]4[CH2:8]3)[CH:18]=[CH:19][C:20]2=[N:25][N:24]=1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC2CN(c3ccc4nnc(C(F)(F)F)n4n3)CC2C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (3.15 g, 14.83 mmol) was added to a mixture of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (3 g, 13.48 mmol) and diisopropyethylamine (4.66 mL, 26.96 mmol) and ethanol (50 mL). The mixture was warmed to 70° C. over a period of 10 minutes, stirred at 70° C. for 1 hour, and then allowed to cool to ambient temperature to give a precipitate. The precipitate was collected by filtration, washed with ethanol (50 mL), and dried under vacuum to afford tert-butyl 5-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (3.00 g, 55.9%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:4](=[O:31])[C:3]=1[CH3:32].[H-].[Na+].[C:35](Cl)(=[O:37])[CH3:36]>C1COCC1.CCOC(C)=O>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[N:7][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:5]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:4](=[O:31])[C:3]([CH3:32])=[C:2]3[NH:1][C:35](=[O:37])[CH3:36])=[CH:17][CH:16]=1
Reactant: Cc1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(CC(C)C)c1=O
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1c(C)c(=O)n(CC(C)C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12

Procedure:
To the product of EXAMPLE 42 (28 mg) in THF (0.5 mL) at 0° C. was added NaH (5 mg, 60% dispersion in mineral oil). The reaction stirred 10 minutes before acetyl chloride (7 μL) was added. Two hours later an additional 20 μL portion of acetyl chloride was added and again after an additional 90 minutes. After an additional hour of reaction time the reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution and dried (Na2SO4). The concentrated residue was purified by preparative TLC on silica gel eluted with 70% EtOAc in hexane affording the title compound. HPLC/MS: 528.0 (M+1), 530.0 (M+3); Rt=4.27 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([C:12](=[O:17])[C:13]([F:15])([F:16])[F:14])[CH2:22][CH:21]=[CH2:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)NCCNC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCN(CCNC(=O)OC(C)(C)C)C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
Dissolve N-(t-butyloxycarbonyl)-N'-(trifluoroacetyl)ethylenediamine (500 mg, 1.95 mmol) in anhydrous dimethylformamide (10 mL), cool to 0° C. and treat with sodium hydride (56 mg, 1.85 mmol, 80% dispersion in mineral oil). Stir for 15 minutes and add allyl bromide (0.25 mL, 2.9 mmol). Stir for 2.5 hours, dilute with ethyl acetate (50 mL) and extract with water (25 mL). Separate the organic phase and wash with brine (2×20 mL). Extract the combined aqueous phases with ethyl acetate (2×5 mL), dry (Na2SO4) and evaporate the solvent in vacuo. Purify by chromatography (2:1 hexane/ethyl acetate to 3:2 hexane/ethyl acetate) to give N-(t-butyloxycarbonyl)-N'-(trifluoroacetyl)-N'-(allyl)ethylenediamine (562mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:16])[NH:5][C:6](=[O:15])[NH:7]2>CN(C=O)C.[Pd]>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:16])[NH:5][C:6](=[O:15])[NH:7]2
Reactant: Nc1c([N+](=O)[O-])ccc2[nH]c(=O)[nH]c(=O)c12
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc2[nH]c(=O)[nH]c(=O)c2c1N
Yield: 96 %

Procedure:
A suspension of the above amine (450 mg, 2.0 mmol) in DMF (15 mL) was hydrogenated over 10% Pd/C (60 mg) at 50 psi for 20 h. The catalyst was removed by filtration and the solvent removed to give 5,6-diaminoquinazolin-2,4-dione (369 mg, 95%) as a dark solid.