Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].Br[C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[O:10][C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(C)(C)Br
Reactant: Cc1cc(C)c(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C(C)(C)Oc1cc(C)cc(C)c1C
Reaction time: 36 h
Yield: 87.2 %

Procedure:
To a solution of 2,3,5-trimethylphenol (20.0 g, 147 mmol) in dimethylsulfoxide (100 ml) was added methyl 2-bromoisobutyrate (52.2 g, 288 mmol) and potassium carbonate (40.0 g, 289 mmol) at room temperature. The mixture was stirred for 36 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using basic silica gel column chromatography (hexane/ethyl acetate=50/1) to obtain 30.3 g (yield 87%) of oily title compound.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C1COCCN1
Solvent: CC(C)=O
Product: Clc1nc(Cl)nc(N2CCOCC2)n1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
Cyanuric chloride (7.36 g, 39.9 mmol) was dissolved in acetone (120 ml), cooled to -15° C. and gradually added dropwise with morpholine (7.00 ml, 80.3mmol) dissolved in acetone (20 ml). This reaction mixture was stirred at the same temperature for 30 minutes and then stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure. The residue was added with dichloromethane and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography, using n-hexane and ethyl acetate (8: 2) as eluant, to obtain 6.33 g (yield: 67.5%) of 2,4-dichloro-6-morpholino-1,3,5-triazine as colorless crystals having melting point of 160.5° C.-161° C.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4].[Cl:19][C:20]1[CH:25]=[C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=1[O:31][CH2:32][CH2:33][CH2:34]I>>[C:15]([C@@:5]1([C:3]([OH:2])=[O:4])[CH2:9][C:8]2[CH:10]=[C:11]([O:14][CH2:34][CH2:33][CH2:32][O:31][C:21]3[CH:22]=[CH:23][C:24]([CH2:26][C:27]([F:28])([F:29])[F:30])=[CH:25][C:20]=3[Cl:19])[CH:12]=[CH:13][C:7]=2[O:6]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: FC(F)(F)Cc1ccc(OCCCI)c(Cl)c1
Reactant: COC(=O)C1(C(C)(C)C)Cc2cc(O)ccc2O1
Product: CC(C)(C)[C@@]1(C(=O)O)Cc2cc(OCCCOc3ccc(CC(F)(F)F)cc3Cl)ccc2O1

Procedure:
The title compound was prepared following the general procedure described in Example 1, Step 4, employing the chiral phenol prepared in step 1 and the iodide prepared in Example 14, Step 2.
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH:5]([NH:16]C(=O)OC(C)(C)C)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)=[O:2].[ClH:24]>ClCCl.O1CCOCC1>[ClH:24].[NH2:16][CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:7]=1)[CH2:4][NH:3][CH:1]=[O:2]
Reactant: CC(C)(C)OC(=O)NC(CNC=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(CNC=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Of the compound from Example 23A, 66 mg (0.2 mmol) were introduced in 1.5 ml of dichloromethane and admixed at RT with 1.56 ml of a 4N solution of hydrogen chloride in dioxane. The reaction mixture was stirred at RT for 1 h. The reaction mixture was freed from the volatile components on a rotary evaporator and dried in an HV. This gave 50 mg (94% of theory) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2F)n1
Reactant: O=C(Cl)Oc1ccccc1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2F)n1
Yield: 64.9 %

Procedure:
Using the procedure in Example 118A, 3-tert-butyl-1-(2-fluorophenyl)-1H-pyrazol-5-amine (1.23 g, 5.27 mmol) and phenyl chloroformate (2.0 mL, 16.0 mmol) were reacted to give phenyl 3-tert-butyl-1-(2-fluorophenyl)-1H-pyrazol-5-ylcarbamate (1.21 g, 3.42 mmol, 59%). 1H NMR (300 MHz, DMSO-d6) δ 10.13 (s, 1H), 7.55-7.35 (m, 6H), 7.23 (t, 1H), 7.08 (br s, 2H), 6.34 (s, 1H), 1.29 (s, 9H); LC-MS (ESI) m/z 354 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH2:9][C:8]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=2[C:6]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[N:5][N:4]=1)=[O:2].[BH4-].[Na+]>O1CCCC1.O>[OH:2][CH2:1][C:3]1[CH2:9][C:8]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=2[C:6]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[N:5][N:4]=1
Reactant: O=CC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(C2=NN=C(CO)Cc3ccc(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
2.15 g (6.6 mM) of 4-formyl-8-chloro-1-(4-nitrophenyl)-5H-2,3-benzodiazepine [prepared according to Step a)] were dissolved in 88 ml of a mixture of tetrahydrofuran and water (1:1), then under ice chilling 0.12 g (3.3 mM) of sodium borohydride was added portion-wise. The reaction mixture was stirred at 25° C. for 40 minutes then it was diluted with 90 ml of water. The precipitated crystals were filtered and purified on a Kieselgel column using a mixture of benzene and ethyl acetate (1:1) as eluant.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9][CH2:10][OH:11].C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH2:18]([N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9][CH2:10][OH:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCCC1CCCCN1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OCCCC1CCCCN1Cc1ccccc1

Procedure:
To a stirred solution of compound 21 (3 g, 16.71 mmol) in ethanol (23 mL) was added K2CO3 (11.5 g, 83.55 mmol) portion-wise at ice cold conditions. Benzyl bromide (2 mL, 16.71 mmol) was then added and the reaction mixture was heated at reflux for 2 hours. The reaction mixture was filtered, and washed with EtOAc. The filtrate was concentrated, the residue was dissolved in EtOAc, washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by 230-400 silica gel column chromatography using 1-3% MeOH-DCM as eluent to yield compound 22.
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([NH2:16])[CH2:14][NH2:15]>C(O)C>[CH2:13]([NH:16][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:14][NH:15][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: NCCN
Reactant: CCCCCCCCCC1CO1
Solvent: CCO
Product: CCCCCCCCCC(O)CNCCNCC(O)CCCCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-undecene oxide (40 g.) and ethylenediamine (7.07 g.) and two recrystallizations of the resulting solid (14.9 g.) from ethanol gave N,N'-ethylenebis[2-hydroxyundecylamine] (I: R = CH3 (CH2)8, R' = H, X = (CH2)2, Z = H) (12.4 g., m.p. 130.2°-137.8° C. ).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=O)[CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO>[F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([NH2:29])[CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 50 °C
Reaction time: 26 h
Yield: 69.4 %

Procedure:
To a mixture of 552.0 mg (1.779 mmol) 1-[4-(4-trifluoromethoxy-benzyloxy)-phenyl]-ethanone and molecular sieves in 10 ml methanol were added 1679.0 mg (21.35 mmol) ammonium acetate and 78.0 mg (1.241 mmol) sodium cyanoborohydride and the reaction mixture was stirred 26 h (HPLC control) at 50° C. After cooling to room temperature, the molecular sieves were filtered off and washed with methanol. The solvent of the combined filtrates was evaporated and diethyl ether and water were added to the residue. While stirring the mixture was acidified with 6N aqueous HCl solution to pH2. The aqueous phase was separated and the organic phase was extracted two times with 1N aqueous HCl solution. Ethyl acetate was added to the combined aqueous phases and the mixture was basified with 6N NaOH to pH 10. The organic phase was separated and the aqueous phase was extracted two more times with ethyl acetate. The combined organic phases were dried over MgSO4 and the solvent evaporated at reduced pressure to afford 268.0 mg (0.861 mmol) 1-[4-(4-trifluoromethoxy-benzyloxy)-phenyl]-ethylamine.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH:17]1[CH2:19][CH2:18]1)=[CH:6]2)#[N:2].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([C:32](O)=O)[CH:29]=[N:30][CH:31]=1>>[CH:17]1([C:7]2[N:8]([CH2:12][C:13]3[N:16]=[C:32]([C:28]4[CH:29]=[N:30][CH:31]=[C:26]([C:25]([F:36])([F:24])[F:35])[CH:27]=4)[O:15][N:14]=3)[C:9]3[C:5]([CH:6]=2)=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH2:19][CH2:18]1
Reactant: O=C(O)c1cncc(C(F)(F)F)c1
Reactant: N#Cc1ccc2c(cc(C3CC3)n2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2noc(-c3cncc(C(F)(F)F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-2-cyclopropyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 364B) and 5-(trifluoromethyl)-3-pyridinecarboxylic acid: MS (ES) m/z 478 (M+1).
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)C(C)=C)[CH2:2][CH2:3]C.Br[C:18]1[CH:25]=[C:22]([CH:23]=[O:24])[C:21]([O:26][CH3:27])=[CH:20][CH:19]=1.CCOCC.[F-].[K+]>C1(C)C=CC=CC=1>[C:2]([C:18]1[CH:25]=[C:22]([CH:23]=[O:24])[C:21]([O:26][CH3:27])=[CH:20][CH:19]=1)([CH3:3])=[CH2:1]
Reactant: C=C(C)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc(Br)cc1C=O
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=C(C)c1ccc(OC)c(C=O)c1
Reaction time: 3 h

Procedure:
Tri-n-butyl-isopropenyltin (12.1 g, 36.6 mmol) dissolved in toluene (10 ml) was added to a mixture of 5-bromo-o-anisaldehyde (6.00 g, 27.9 mmol), tetrakis (triphenylphosphine)palladium (1.21 g, 1.05 mmol), and 2,6-t-butyl4-methylphenol (10 mg) in toluene (50 ml) under nitrogen at room temperature. This mixture was heated at reflux for 7 hr. Ether and aq. KF solution (80 ml) were added to the reaction mixture, and the resulting solution was stirred for 3 hr. Insoluble materials were removed by filtration through Celite. The filtrate was extracted with ether, and the organic phase was washed with 1N-NaHSO4 aq. NaHCO3 and brine. The extracts were dried over Na2SO4, and concentrated by evaporation. The residual oil was purified by chromatography (SiO2, 140 g, 5%-EtOAc/hexane) to afford 5-isopropenyl-o-anis-aldehyde, as a yellow oil (2.49 g, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])=[O:4].[Cl-].[NH4+].O.[C:17](OCC)(=O)C>>[C:7]([C:6]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[CH3:17]
Reactant: COC(=O)c1ncccc1C(=O)Cl
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COC(=O)c1ncccc1C(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium methylsulfonylmethyl(methyl)cuprate(I) is chilled to -78°, and 2-methoxycarbonylnicotinoyl chloride (3.2 g, 16.0 mmol) is slowly added, keeping the temperature at -65° to -70°. The mixture is stirred at -78° for 1 hour, after which aq. ammonium chloride is added. The mixture is warmed to RT, poured into water and ethyl acetate and extracted with ethyl acetate. The combined organic phases are dried and reduced and the product is purified by prep. TLC to give methyl 3-acetyl-2-pyridinecarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([CH:24]=[C:25]([C:27]([O:29]CC)=[O:28])[N:26]=2)[CH:12]=[C:13]([C:15]2[S:19][C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])=[N:17][CH:16]=2)[CH:14]=1.[OH-].[Na+]>CO.C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([CH:24]=[C:25]([C:27]([OH:29])=[O:28])[N:26]=2)[CH:12]=[C:13]([C:15]2[S:19][C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])=[N:17][CH:16]=2)[CH:14]=1
Reactant: CCOC(=O)c1cn2cc(-c3cnc(CC(C)C)s3)cc(-c3ccc(F)cc3F)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Cc1ncc(-c2cc(-c3ccc(F)cc3F)c3nc(C(=O)O)cn3c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of ethyl 8-(2,4-difluorophenyl)-6-(2-isobutylthiazol-5-yl)imidazo[1,2-a]pyridine-2-carboxylate (47.7 mg, 0.108 mmol) in MeOH (2 mL) and THF (2 mL) was added 1N NaOH (2 mL). The mixture was stirred at room temperature overnight. The mixture was concentrated, diluted with EtOAc (10 mL), washed with water (5 mL) and concentrated. The residue was purified by prep HPLC to give a white solid as a TFA salt form (32 mg, 56% yield). LCMS (Conditions C): Tr 3.55 min; (M+H)+=414.29 (100%), 415.37 (20%), 416.26 (10%). 1H NMR, 400 MHz, CDCl3: 8.37 (d, J=1.5 Hz, 1H), 8.33 (s, 1H), 7.92 (s, 1H), 7.88 (m, 1H), 7.61 (s, 1H), 7.13-7.03 (m, 2H), 2.96 (d, J=7.1 Hz, 2H), 2.18 (m, 1H), 1.06 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([O:15][C:16]([F:19])([F:18])[F:17])[CH:9]=2)[CH2:4][CH2:3]1.[N:20]#[C:21][NH2:22]>Cl.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:21]([NH2:22])=[NH:20])=[C:10]([O:15][C:16]([F:19])([F:17])[F:18])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: N#CN
Reactant: CN1CCN(c2ccc(N)c(OC(F)(F)F)c2)CC1
Agent: Cl
Solvent: O
Product: CN1CCN(c2ccc(NC(=N)N)c(OC(F)(F)F)c2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a solution of 4-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamine (275 mg, 1 mmol) in HCl 6N (1 mL), cyanamide (336 mg, 8.0 mmol) was added and the reaction was stirred at 60° C. for 1 hours. The mixture was cooled down to room temperature, diluted with H2O (3 mL), extracted with DCM (10 mL). NaOH 2N was added to pH>11. The aqueous phase was extracted with Et2O (3×10 mL), dried over Na2SO4 and concentrated. The residue was crystallized from Et2O to give the title compound (240 mg, 76% yield) as a white solid.
Reaction SMILES: C1(C)C=CC=CC=1.[Br:8][CH2:9][C:10]([OH:12])=[O:11].[CH2:13](O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:11]
Reactant: O=C(O)CBr
Reactant: CCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(=O)CBr
Reaction time: 1.5 h
Yield: 113.4 %

Procedure:
There were added to 150 ml of toluene, 20 g of bromoacetic acid, 20 g of n-octyl alcohol and 2.5 g of p-toluenesulfonic acid, and azeotropical dehydration was carried out for 1.5 hours. After cooling, toluene was distilled off at reduced pressure, and 41 g of n-octyl bromoacetate were obtained by vacuum distillation (110° C., 11 mm Hg).
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:31]1([CH2:37][S:38](Cl)(=[O:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1.O>[CH3:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:38]([CH2:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:40])=[O:39])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: COc1cccc(-c2c(C)sc3nc(C)cc(N)c23)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)Cc4ccccc4)c23)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.5 %

Procedure:
To a stirred solution of 2,6-dimethyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (100 mg, 0.352 mmol) (Description 4) in THF (2 mL) cooled in an ice bath was added LiHMDS (1M solution in THF) (0.774 mL, 0.774 mmol). The reaction mixture was stirred at RT for 45 min before the addition of phenylmethanesulfonyl chloride (168 mg, 0.879 mmol). The reaction mixture was stirred at RT for a further 16 h and was then cooled in an ice bath before the addition of LiHMDS (1M solution in THF) (0.352 mL, 0.352 mmol). The reaction mixture was then stirred at RT for 1 h before the addition of phenylmethanesulfonyl chloride (67.2 mg, 0.352 mmol). The reaction mixture was stirred at RT for a further 16 h and then diluted with water (10 mL) and the aqueous layer extracted with DCM (3×20 mL). The combined organic extracts were dried over a phase separating column and concentrated. The residue was purified by MDAP (basic conditions), to afford the title compound (10 mg). LCMS (A) m/z: 439 [M+1]+, Rt 1.31 min (basic).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([CH:14]=[O:15])[CH3:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>O.[Pd]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([CH3:13])[CH:14]=[O:15])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C=O)=Cc1ccc(C(C)(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Temperature: 110 °C
Yield: 88.9 %

Procedure:
1420 g of 1-(p-tert.butylphenyl)-2-formyl-1-propene, prepared as described in paragraph (e), are mixed together with 6 g of 5% palladium/carbon and 6.8 g of soda in 20 ml of water at 70°-75° C. in a stirring autoclave. The autoclave is charged with hydrogen (8 atmospheres) and heated to 110° C. About 230 liters of hydrogen are absorbed after 12 hours. The crude 3-(p-tert.butyl-phenyl)-2-methyl-propionaldehyde is treated with ether, washed neutral with water and dried over sodium sulphate. After removing the ether, the product is fractionally distilled in vacuo. After separating a first running and a last running, there are obtained 1275 g of 3-(p-tert.butylphenyl)-2-methyl-propionaldehyde in 95% purity (about 88% of theory). Boiling point: 150°-152° C./15 mmHg; nD20 =1.5050.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:13][N:12]=1.N>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:13][N:12]=1
Reactant: NCc1cccc(Cl)c1
Reactant: Clc1ncc(Cc2ccncc2)c2ccccc12
Agent: N
Solvent: CCOC(C)=O
Product: Clc1cccc(CNc2ncc(Cc3ccncc3)c3ccccc23)c1

Procedure:
With the exclusion of moisture, 1.6 ml (13.1 mmol) of 3-chlorobenzylamine and 800 mg (3.14 mmol) of 1-chloro-4-(pyridin-4-ylmethyl)-isoquinoline (Example 1e) are stirred for 2 hours at 150° C. The mixture is suspended in ethyl acetate, 1 ml of concentrated ammonia solution is added, washing with water and brine is carried out, and the organic phase is dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; ethyl acetate) yields the title compound: m.p. 141-142° C.; 1H NMR (DMSO-d6) 8.39 (d, 2H), 8.31 (d, 1H), 8.03 (t, HN), 7.82 (s, 1H), 7.69 (d, 1H), 7.61 (t, 1H), 7.50 (t, 1H), 7.40 (s, 1H), 7.33 (m, 2H), 7.26 (m, 1H), 7.20 (d, 2H), 4.73 (d, 2H), 4.14 (s, 2H); FAB-MS: (M+H)+=360; Anal. calc. (C22H18N3Cl) C 73.43%, H 5.04%, N 11.68%, Cl 9.85%; found C 73.2%, H 5.1%, N 11.6%, Cl 9.9%.
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6]([C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[N:15]=[C:16]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:17]([CH3:23])=[N:18]3)=[CH:7][C:8]=1[C:9]([O:11]C)=O)(=O)[CH3:2].O.[NH2:30][NH2:31]>C(O)C>[C:25]([NH:24][C:16]1[C:17]([CH3:23])=[N:18][C:19]2[C:14]([N:15]=1)=[C:13]([C:6]1[NH:5][C:4]3[C:1]([CH3:2])=[N:30][NH:31][C:9](=[O:11])[C:8]=3[CH:7]=1)[CH:22]=[CH:21][CH:20]=2)([CH3:27])([CH3:28])[CH3:26]
Reactant: NN
Reactant: COC(=O)c1cc(-c2cccc3nc(C)c(NC(C)(C)C)nc23)[nH]c1C(C)=O
Solvent: O
Solvent: CCO
Product: Cc1nc2cccc(-c3cc4c(=O)[nH]nc(C)c4[nH]3)c2nc1NC(C)(C)C
Temperature: 75 °C
Yield: 24.6 %

Procedure:
A mixture of methyl 2-acetyl-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (416b) (0.141 g, 0.37 mmol), hydrazine monohydrate (Fluka, 0.020 mL, 0.408 mmol) in Ethanol (1.23 mL) was heated to 75° C. for 24 h. Reaction mixture was directly loaded on silica gel samplet and purified by Biotage (30-100% EtOAc:EtOH (3:1)/hexanes) to produce 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-7-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (416) (33 mg, 0.091 mmol, 24% yield) that solidified as yellow solid upon drying. 1H NMR (300 MHz, MeOH) δ ppm 1.67 (s, 9H) 2.56-2.70 (m, 1H) 7.30-7.40 (m, 1H) 7.40-7.50 (m, 1H) 7.40-7.55 (m, 1H) 7.76-7.87 (m, 1H) 8.03-8.16 (m, 1H). m/z (ESI, +ve) 363.0 (M+H).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C@@H:5]([CH3:7])[C@H:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[S:3]1.[CH:15]1([N:21]=[C:22]=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C1C=CC=CC=1.C(N(CC)CC)C>[CH:15]1([NH:21][C:22]([N:1]=[C:2]2[N:6]([C:22](=[O:23])[NH:21][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C@@H:5]([CH3:7])[C@H:4]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)[S:3]2)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C=NC1CCCCC1
Reactant: Cc1ccc([C@@H]2SC(=N)N[C@H]2C)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1ccc([C@@H]2SC(=NC(=O)NC3CCCCC3)N(C(=O)NC3CCCCC3)[C@H]2C)cc1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
1.0 g of trans-2-imino-4-methyl-5-(4-methylphenyl)thiazolidine was dissolved in 20 ml of benzene. To the solution were added 1.3 g of cyclohexylisocyanate and one drop of triethylamine, respectively. The mixture was stirred for an hour at room temperature and refluxed for further an hour. The reaction solution was condensed under reduced pressure. The oily product obtained was purified by column chromatography to give 1.1 g of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(O)C>[C:22]([NH:1][CH2:2][C:3]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:5][CH2:4]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccccc2)CC1
Solvent: CCO
Product: CC(=O)NCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
8 g tert-butyl 4-aminomethyl-4-phenylpiperidine-1-carboxylate and 2.9 ml acetic anhydride are stirred in 80 ml of ethanol overnight at ambient temperature and then evaporated to dryness. 10.4 g product are obtained.