Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH3:6].[CH3:7][C:8]1[O:9][CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[N:16]=[C:15]1[NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[OH2:4].[OH2:9].[CH2:5]([O:4][CH2:3][CH2:2][N:27]1[CH2:26][CH2:25][CH:24]([NH:23][C:15]2[N:14]([CH2:13][C:12]3[CH:11]=[CH:10][O:9][C:8]=3[CH3:7])[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH2:29][CH2:28]1)[CH3:6]
Reactant: Cc1occc1Cn1c(NC2CCNCC2)nc2cccnc21
Reactant: CCOCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCN1CCC(Nc2nc3cccnc3n2Cc2ccoc2C)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
A mixture of 1.2 parts of 1-chloro-2-ethoxyethane, 3.1 parts of 3-[(2-methyl-3-furanyl)methyl]-N-(4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amine, 1.6 parts of sodium carbonate and 45 parts of N,N-dimethylformamide was stirred overnight at 70° C. The reaction mixture was poured into 50 parts of water. Petroleum ether was added and after stirring, the crystallized product was filtered off, washed with water and petroleum ether and stirred in 1,1'-oxybisethane. The product was filtered off and dried at room temperature, yielding 1.6 parts (38.1%) of N-[1-(2-ethoxyethyl)-4-piperidinyl]-3-[(2-methyl-3-furanyl)methyl]-3H-imidazo-[4,5-b]pyridin-2-amine dihydrate; mp. 84.5° C. (compound 32).
Reaction SMILES: [C:1]1([C:7]2[NH:23][C:10]3[N:11]=[CH:12][N:13]=[C:14]([O:15][C:16]4[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=4)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C(#N)C>[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:14]3[C:9]4[CH:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[NH:23][C:10]=4[N:11]=[CH:12][N:13]=3)=[CH:17][CH:18]=2)=[O:33])=[CH:27][CH:26]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ncnc3[nH]c(-c4ccccc4)cc23)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ncnc3[nH]c(-c4ccccc4)cc23)cc1
Reaction time: 1 h

Procedure:
After dissolving 40 mg of 4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine in 4.5 ml of toluene and 4.5 ml of acetonitrile at 110° C., 4-fluorophenyl isocyanate (16.6 μl) was added and the mixture was stirred for 1 hour. After returning the mixture to room temperature, the precipitated crystals were filtered out and dried to obtain 37 mg of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2].[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][Br:29]>>[Br-:29].[C:1]([C:4]1[CH:5]=[N+:6]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([F:24])[CH:26]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCC(Cc1ccncc1C(C)=O)C2=O
Reactant: Fc1cccc(CBr)c1
Product: COc1ccc2c(c1)CCC(Cc1cc[n+](Cc3cccc(F)c3)cc1C(C)=O)C2=O
Product: [Br-]

Procedure:
The title compound 128 is prepared according to the procedure reported in Example 38.1 with compound 103 (62 mg, 0.2 mmol) and 3-fluorobenzyl bromide (37 μL, 0.3 mmol) as reactants. White solid. (Yield 83.1 mg, 83%).
Reaction SMILES: [F:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH3:19]C(OC(C)=O)=O.C(OCC)(OCC)OCC.[NH2:36][C:37]([CH3:42])([CH3:41])[CH2:38][CH2:39][OH:40]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([C:6](=[CH:19][NH:36][C:37]([CH3:42])([CH3:41])[CH2:38][CH2:39][OH:40])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(N)CCO
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Solvent: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNC(C)(C)CCO)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
A stirred solution of ethyl (2,3,4,5-tetrafluorobenzoyl)acetate (3.73 g, 14.1 mmol), Ac2O (8.50 mL, 85.7 mmol) and triethyl orthoformate (4.70 mL, 28.2 mmol) was heated at 120° C. for 3 h. The mixture was concentrated in vacuo and dried under high vacuum. To the mixture of the residue in anhydrous toluene (50 mL) was added 3-amino-3-methyl-1-butanol (1.45 g, 14.1 mmol) in anhydrous toluene (20 mL) very slowly at 0° C. and stirred at room temperature for 2 h. The solvent was removed by evaporation. Flash chromatography (EtOAc:Hexane=1:1) of the residue gave ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-[(1-hydroxy-3-methylbutane-3-yl)amino]acrylate as a colorless solid (3.91 g, 73%).
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](O)=[O:4].[C:7]([O:11][C:12](=[O:19])[NH:13][C@@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)([CH3:10])([CH3:9])[CH3:8].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:7]([O:11][C:12](=[O:19])[NH:13][C@@H:14]1[CH2:18][CH2:17][N:16]([C:3](=[O:4])[C@H:2]([OH:1])[CH3:6])[CH2:15]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: C[C@@H](O)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](O)C(=O)N1CC[C@@H](NC(=O)OC(C)(C)C)C1
Yield: 96.9 %

Procedure:
[(R)-1-((R)-2-Hydroxy-propionyl)-pyrrolidin-3-yl]carbamic acid tert-butyl ester (500 mg) was prepared by following General Procedure F starting from (R)-2-hydroxy-propionic acid (200 mg), (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (372 mg), HBTU (800 mg), and DIEA (400 uL) in DMF (4 mL).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.CC1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(=Nc2ccc(Cl)cc2)CC1

Procedure:
A mixture of 171.2 parts of ethyl 4-oxo-1-piperidinecarboxylate, 159.5 parts of 4-chlorobenzenamine, 1520 parts of anhydrous methylbenzene and a few crystals of 4-methylbenzenesulfonic acid is stirred and refluxed for 7 hours. (The reaction vessel is provided with a reflux-condensor and water-separator). The methylbenzene is evaporated and the oily residue is distilled in vacuo, yielding 192 parts of oily ethyl 4-[(4-chlorophenyl)imino]-1-piperidinecarboxylate; bp. 171°-176° C. at 0.4 mm. pressure.
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Mg].CN(C)[CH:20]=[O:21].[Cl-].[NH4+]>O1CCCC1.C(Cl)(Cl)(Cl)Cl>[CH2:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:20]=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CN(C)C=O
Reactant: CCCCCCCCCc1ccccc1Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCCc1ccccc1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A third of a solution of 22 g of 2-nonylbromobenzene in 35 ml of tetrahydrofuran is added to a mixture, stirred under an argon atmosphere, of 3.4 g of magnesium chips, 25 ml of tetrahydrofuran and 3 drops of carbon tetrachloride and the whole is heated at the boil under reflux for 30 minutes. The remainder of the 2-nonylbromobenzene solution is then added dropwise over a period of one hour and the reaction mixture is maintained under reflux for 2 hours. After dilution with 40 ml of tetrahydrofuran the whole is cooled in an ice bath to approximately 5° and a solution of 11.6 ml of dimethylformamide in 20 ml of tetrahydrofuran is added dropwise over a period of 15 minutes. After stirring for one hour at room temperature, 250 ml of saturated ammonium chloride solution are added to the reaction mixture, the organic layer is separated off and the aqueous layer is extracted three times with ether. The residue that remains after the combined ethereal extracts have been dried and concentrated by evaporation is purified by chromatography on silica gel with mixtures of petroleum ether with an increasing amount of methylene chloride, yielding the desired 2-nonylbenzaldehyde in the form of a pale yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1I.C([Mg]Cl)(C)C.[CH:32]([N:45]1[CH2:48][C:47](=[O:49])[CH2:46]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH:32]([N:45]1[CH2:48][C:47]([C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH2:13][C:12]([C:18]4[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=4)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=3)=[CH:3][C:2]=2[Br:1])([OH:49])[CH2:46]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CC(c2ccc(I)c(Br)c2)=NO1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Br)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -40 °C
Reaction time: 1.5 h

Procedure:
In an oven-dried flask containing 3-(3-bromo-4-iodophenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (1000 mg, 1.67 mmol) in THF (25 mL) at −40° C. was slowly added isopropyl magnesium chloride (1.7 mL of 2.0M solution). The reaction was stirred at approximately −40° C. for 1.5 hours under nitrogen. 1-benzhydrylazetidin-3-one (520 mg in 4 mL THF) was slowly added. The reaction was stirred at −40° C. for an additional 30 minutes and allowed to warm to room temperature. Stirring was continued for 2 hours at room temperature. The reaction was quenched with saturated NH4Cl and extracted with EtOAc (2×75 mL). The combined organic phase was dried (Na2SO4) and concentrated under vacuum. The crude material was chromatographed (40 g Redi-Sep column) eluting from 100% heptane to 60:40 EtOAc:heptane, collecting the intermediate (615 mg, 52%) as a glass. 1HNMR (CDCl3) δ ppm: 7.87 (1H), 7.66-7.63 (3H), 7.45 (4H), 7.36-7.21 (7H), 4.39 (1H), 4.07 (1H), 3.73-3.58 (5H), 3.06 (1H); m/z (CI) 711 [M+H]+.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27]([OH:29])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([NH2:39])[C:33]([CH3:38])([CH3:37])[CH2:34][O:35][CH3:36]>>[CH3:36][O:35][CH2:34][C:33]([C:32]1[N:39]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)[O:29][N:31]=1)([CH3:38])[CH3:37]
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Reactant: COCC(C)(C)C(N)=NO
Product: COCC(C)(C)c1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
80 mg (0.188 mmol) of the compound from Example 100A and 41 mg (0.281 mmol) of N′-hydroxy-3-methoxy-2,2-dimethylpropanimidamide were reacted according to the General Method 2. Yield: 55 mg (56% of theory)
Reaction SMILES: [Si]([N:8]1[CH:11]([CH2:12][C:13](=[O:25])[CH2:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH:10]([N:26]=[N+:27]=[N-:28])[C:9]1=[O:29])(C(C)(C)C)(C)C.Cl>CO.O>[N:26]([CH:10]1[CH:11]([CH2:12][C:13](=[O:25])[CH2:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[NH:8][C:9]1=[O:29])=[N+:27]=[N-:28]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CC(=O)CC(=O)OCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: [N-]=[N+]=NC1C(=O)NC1CC(=O)CC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
A solution of N-(t-butyldimethylsilyl)-3-azido-4-(3-benzyloxycarbonyl-2-oxopropyl)azetidin-2-one (1.0 g) in methanol (10 ml) is treated with conc. hydrochloric acid (0.1 ml) and left at room temperature for 2 hr. The solution is diluted with water and extracted with ethyl acetate. The extracts are washed with 5% sodium bicarbonate solution and brine, dried, and evaporated under vacuum. The residue is chromatographed on silica gel to give 3-azido-4-(3-benzyloxycarbonyl-2-oxopropyl)-azetidin-2-one.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccccc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccccc1Oc1ccc(C(F)(F)F)cc1N
Yield: 251.5 %

Procedure:
Title compound 38 (1.70 g, 1.98 mmol), Pd (C) 10% (0.17 g, 10% w/w) and MeOH were put in a Parr-Shaker apparatus and the reaction mixture was pressurized to 55 PSI of H2. The mixture was agitated over night. The catalyst was filtered and the filtrate was concentrated to afford title compound 39 (1.55 g, 100%) as a clear oil. LRMS (ESI): (calc) 311.08. (found) 312.1 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH2:25][CH2:26][CH2:27][CH3:28])[CH:5]=[CH:4][C:3]=1[C:29]1[NH:33][C:32](=[O:34])[O:31][N:30]=1.[Cu](C#N)[C:36]#[N:37]>N1C=CC=CC=1>[CH2:25]([C:11]1[N:12]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)[S:14][C:10]=1[CH2:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([C:29]2[NH:33][C:32](=[O:34])[O:31][N:30]=2)=[C:2]([CH:7]=1)[C:36]#[N:37])[CH2:26][CH2:27][CH3:28]
Reactant: N#C[Cu]C#N
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2noc(=O)[nH]2)c(Br)c1
Solvent: c1ccncc1
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2noc(=O)[nH]2)c(C#N)c1
Temperature: 21 °C
Yield: 10.5 %

Procedure:
To a solution of 100 mg of 3-{2-bromo-4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one in 4 ml of pyridine was added 29 mg of copper cyanide. The resulting mixture was stirred under microwave heating at 21° C. for 10 minutes, then concentrated under reduced pressure. The residue was taken into ethyl acetate, washed with a pH 9 aqueous solution of ammonia, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography on silica gel (dichloromethane 95/methanol 5) and precipitated from ethyl acetate/diisopropyl ether/pentane to give 9.5 mg of 5-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzonitrile
Reaction SMILES: [F:1][CH:2]([F:37])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]3[O:20][N:19]=[C:18]([CH2:21][CH2:22][O:23][CH3:24])[N:17]=3)[CH2:13][N:12]([C:25](OC3C=CC([N+]([O-])=O)=CC=3)=[O:26])[CH2:11]2)=[CH:6][CH:5]=1.[NH:38]1[CH2:43][CH2:42][S:41][CH2:40][CH2:39]1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[F:1][CH:2]([F:37])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]3[O:20][N:19]=[C:18]([CH2:21][CH2:22][O:23][CH3:24])[N:17]=3)[CH2:13][N:12]([C:25]([N:38]3[CH2:43][CH2:42][S:41][CH2:40][CH2:39]3)=[O:26])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: COCCc1noc(C2CC(c3ccc(CC(F)F)cc3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)n1
Reactant: C1CSCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COCCc1noc(C2CC(c3ccc(CC(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1
Temperature: 150 °C

Procedure:
A solution of 56.0 mg (0.065 mmol, purity 60%) of the compound from Example 62A in 1-methyl-2-pyrrolidone (2.0 ml) was admixed with 37.0 μl (40.0 mg, 0.390 mmol) of thiomorpholine and 34.0 μl (25.0 mg, 0.195 mmol) of N,N-diisopropylethylamine and then heated in a single-mode microwave (Emrys Optimizer) at 150° C. for 30 min. For workup, the reaction solutions were combined and purified directly by means of preparative HPLC. Yield: 14.7 mg (47% of theory)
Reaction SMILES: Br[C:2]1[C:3]([CH:14]([F:16])[F:15])=[N:4][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:6]=1[CH3:7].[O:17]1CCC[CH2:18]1.C([Li])CCC.CN(C)C=O>CCCCCC>[F:15][CH:14]([F:16])[C:3]1[C:2]([CH:18]=[O:17])=[C:6]([CH3:7])[N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[N:4]=1
Reactant: C1CCOC1
Reactant: Cc1c(Br)c(C(F)F)nn1C1CCCCO1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1c(C=O)c(C(F)F)nn1C1CCCCO1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A solution of 4-bromo-3-(difluoromethyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0.60 g, 2.0 mmol) in tetrahydrofuran (7.00 mL, 86.3 mmol) was cooled at −78° C. Into the reaction was added 1.6 M of n-butyllithium in hexane (2.00 mL) and was stirred at −78° C. for 5 min. N,N-Dimethylformamide (0.31 mL, 4.1 mmol) was added and stirred at −78° C. for 1 h. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The crude product was used in the next reaction without further purification. 1H NMR (CDCl3): δ 10.12 (s, 1H), 6.81-6.95 (t, 1H), 5.38 (m, 1H), 4.03 (m, 1H), 3.68 (m, 1H), 2.66 (s, 3H), 2.42 (m, 1H), 2.14 (m, 1H), 1.96 (m, 1H), 1.50-1.75 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH3:13])=[C:10]([F:29])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:30](Cl)(=[O:32])[CH3:31]>N1C=CC=CC=1>[F:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([N:23]4[CH2:28][CH2:27][N:26]([C:30](=[O:32])[CH3:31])[CH2:25][CH2:24]4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH3:13])=[C:10]([F:29])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCNCC3)nn12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)N1CCN(c2ccc3ncc(C(C)c4c(F)cc5ncccc5c4F)n3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(rac)-5,7-Difluoro-6-[1-(6-piperazin-1-yl-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-quinoline (Example 6, 50 mg, 0.127 mmol) was dissolved in pyridine (1.27 mL) and acetyl chloride (0.014 mL, 0.190 mmol) was added. The RM was stirred at RT for 0.5 h. The mixture was concentrated and the residue was purified by flash chromatography and afforded the title compound as a beige foam (tR 3.36 min (conditions 1), MH+ 437).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].Cl.Cl.Cl.[F:11][C:12]1[CH:36]=[CH:35][CH:34]=[CH:33][C:13]=1[CH2:14][C:15]1[N:19]2[N:20]=[CH:21][CH:22]=[CH:23][C:18]2=[C:17]([C:24]2[N:29]=[C:28]([NH2:30])[C:27]([NH2:31])=[C:26]([NH2:32])[N:25]=2)[N:16]=1>N1C=CC=CC=1>[CH:2]([OH:4])=[O:3].[NH2:32][C:26]1[C:27]([NH:31][C:2](=[O:3])[O:4][CH:5]([CH3:7])[CH3:6])=[C:28]([NH2:30])[N:29]=[C:24]([C:17]2[N:16]=[C:15]([CH2:14][C:13]3[CH:33]=[CH:34][CH:35]=[CH:36][C:12]=3[F:11])[N:19]3[C:18]=2[CH:23]=[CH:22][CH:21]=[N:20]3)[N:25]=1
Reactant: Nc1nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc(N)c1N
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1c(N)nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc1N
Product: O=CO

Procedure:
At 0° C., twice at an interval of 10 minutes, in each case 76.4 mg (0.62 mmol) of isopropyl chloroformate were added to 247 mg (0.62 mmol) of 2-[7-(2-fluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidine-4,5,6-triamine (Example 9A) in 4.9 ml of pyridine. The reaction mixture was concentrated and the residue was purified by preparative HPLC (acetonitrile:water (+0.1% formic acid) gradient). This gave 189 mg (63% of theory) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[NH:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.CO.O>[CH2:12]([NH:1][C:2]1[C:10]2[NH:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1nc2cccc(N)c2[nH]1
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: Cc1nc2cccc(NCc3ccccc3)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 1.6 %

Procedure:
A mixture of 3.8 g (0.026 mol) 4-amino-2-methylbenzimidazole, 2.7 g (0.026 mol) benzaldehyde and 0.05 g paratoluene sulfonic acid in 250 ml toluene was refluxed and the water formed was separated during 20 h. Upon cooling the volatiles were removed under reduced pressure. The residue obtained was suspended in 150 ml methanol and 1.8 g (0.048 mol) NaBH4 was added. The mixture was stirred at room temperature for 2 h and methanol was removed under reduced pressure. The residue was dissolved in methylene chloride, washed with water and dried (Na2SO4). After filtration, methylene chloride was removed under reduced pressure. Chromatography on silica gel and elution with methylene chloride:methanol (10:1) gave 0.1 g (0.00042 mol) of 4-benzylamino-2-methyl benzimidazole
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:15]([C:17]3[CH:18]=[C:19]([Cl:35])[C:20]([C:33]#[N:34])=[C:21]4[C:27]=3[O:26][CH:25]([CH3:28])[CH2:24][N:23]([CH:29]3[CH2:32][NH:31][CH2:30]3)[CH2:22]4)[CH3:16])[N:12]=[C:13]([CH3:14])[C:6]=12.C(N(CC)CC)C.[CH3:43][C:44]1([CH3:47])[CH2:46][O:45]1>CN(C)C=O>[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:15]([C:17]3[CH:18]=[C:19]([Cl:35])[C:20]([C:33]#[N:34])=[C:21]4[C:27]=3[O:26][CH:25]([CH3:28])[CH2:24][N:23]([CH:29]3[CH2:32][N:31]([CH2:43][C:44]([OH:45])([CH3:47])[CH3:46])[CH2:30]3)[CH2:22]4)[CH3:16])[N:12]=[C:13]([CH3:14])[C:6]=12
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CN(C2CNC2)C3)c2ncnc(N)c12
Reactant: CC1(C)CO1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CN(C2CN(CC(C)(C)O)C2)C3)c2ncnc(N)c12
Temperature: 85 °C
Reaction time: 4 h

Procedure:
9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-azetidin-3-yl-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile trishydrochloride (0.015 g, 0.034 mmol) was dissolved in N,N-dimethylformamide (1.0 mL) and triethylamine (0.025 mL, 0.18 mmol), and 2,2-dimethyloxirane (0.050 g) was added. The reaction was heated to 85° C. stirred for 4 h. The reaction was concentrated in vacuo, and the product was purified without workup by prep HPLC on a C-18 column eluting water:acetonitrile gradient buffered pH 10 to give the title compound as two diastereomers: Peak #1 (Example 54) (0.002 g, 13%): LCMS calculated for C26H34ClN8O2 (M+H)+: m/z=525.2; found: 525.2; Peak #2 (Example 55) (0.002 g 13%): LCMS calculated for C26H34ClN8O2 (M+H)+: m/z=525.2; found: 525.2.