Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]4[CH2:28][NH:27][CH2:26][CH2:25][N:24]4[CH:29]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:30](N(CC)CC)C.C=O.O.C([BH3-])#N.[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]4[CH2:28][N:27]([CH3:30])[CH2:26][CH2:25][N:24]4[CH:29]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn2c(n1)CNCC2
Reactant: CCN(CC)CC
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn2c(n1)CN(C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide (23 mg, 0.056 mmol) was dissolved in methanol (2 ml). Triethylamine (0.078 ml, 0.561 mmol), formaldehyde, 37 w-% solution in water (0.067 ml, 0.561 mmol) and sodium cyanoborohydride (35.3 mg, 0.561 mmol) were added in the solution. The resulting mixture was stirred at RT overnight. The reaction mixture was diluted with DCM, extracted with NaHCO3 solution, combined organic phases were dried with Na2SO4, filtered and evaporated. The product was purified with LC/MS-trigger. Yield 33.6%. 1H-NMR (400 MHz; CDCl3): δ 1.26 (d, 3H), 2.55 (s, 3H), 2.90 (t, 2H), 3.70 (d, 2H), 4.08 (t, 2H), 4.32 (dd, 1H), 4.40 (dd, 1H), 4.54-4.65 (m, 1H), 6.61 (d, 1H), 7.48 (s, 1H), 7.50 (d, 1H), 7.67 (d, 1H), 7.71 (d, 1H), 7.81 (dd, 1H), 8.02 (d, 1H), 8.06 (s, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([NH2:13])[CH:10]=[C:9]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:8]=2)[CH2:3][CH2:2]1.Cl[C:21]1[N:26]=[C:25]([N:27]([C:29]2[C:37]3[O:36][CH2:35][O:34][C:33]=3[CH:32]=[CH:31][C:30]=2[Cl:38])[CH3:28])[CH:24]=[CH:23][N:22]=1>>[Cl:38][C:30]1[CH:31]=[CH:32][C:33]2[O:34][CH2:35][O:36][C:37]=2[C:29]=1[N:27]([CH3:28])[C:25]1[CH:24]=[CH:23][N:22]=[C:21]([NH:13][C:11]2[CH:10]=[C:9]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:12]=2)[N:26]=1
Reactant: CN(c1ccnc(Cl)n1)c1c(Cl)ccc2c1OCO2
Reactant: Nc1cc(N2CCOCC2)nc(N2CCOCC2)c1
Product: CN(c1ccnc(Nc2cc(N3CCOCC3)nc(N3CCOCC3)c2)n1)c1c(Cl)ccc2c1OCO2
Yield: 25.3 %

Procedure:
2,6-Dimorpholinopyridin-4-amine (160 mg, 0.60 mmol) and 2-chloro-N-(5-chlorobenzo[d][1,3]dioxol-4-yl)-N-methylpyrimidin-4-amine (180 mg, 0.60 mmol) were reacted according to the procedure in Example 1 to give N4-(5-chlorobenzo[d][1,3]dioxol-4-yl)-N2-(2,6-dimorpholinopyridin-4-yl)-N4-methylpyrimidine-2,4-diamine (80 mg, 25.2%) as a pale yellow foam. NMR Spectrum (CDCl3) 3.23-3.58 (m, 11H), 3.72-3.90 (m, 8H), 5.65 (s, 1H), 6.03 (s, 2H), 6.50 (s, 2H), 6.79 (d, 1H), 6.99 (d, 1H), 7.17 (s, 1H), 7.90 (s, 1H); Mass spectrum: MH+ 526.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[CH:13]=1)[O:10][C:9]([C:21](O)=[O:22])=[CH:8][C:7]2=[O:24].[Cl:25][C:26]1[CH:27]=[C:28]([NH2:38])[CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[Cl:25][C:26]1[CH:27]=[C:28]([NH:38][C:21]([C:9]2[O:10][C:11]3[C:6]([C:7](=[O:24])[CH:8]=2)=[CH:5][C:4]([O:3][CH3:2])=[CH:13][C:12]=3[N:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)=[O:22])[CH:29]=[CH:30][C:31]=1[N:32]1[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1
Reactant: Nc1ccc(N2CCOCC2)c(Cl)c1
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)O)cc(=O)c2c1
Agent: Cl
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCOCC4)c(Cl)c3)cc(=O)c2c1

Procedure:
This compound was prepared from 6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 2) and commercially available 3-chloro-4-morpholin-4-yl-phenylamine (Maybridge) as prepared in Example 12, yielding a yellow solid. (45 mg=31%) LCMS-m/z=513.5.
Reaction SMILES: C([NH:8][C@H:9]([CH:14]=O)[CH2:10][CH:11]([CH3:13])[CH3:12])(OC(C)(C)C)=O.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]([CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])[CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[NH2:8][C@@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:14][N:34]1[CH2:33][CH2:32][CH:31]([N:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:29][CH:28]=2)[CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])[CH2:36][CH2:35]1
Reactant: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCNCC1
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C[C@@H](N)CC(C)C)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70.3 %

Procedure:
Boc-L-leucinal (0.78 g. 3.64 mmol) was treated with a solution of (4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-piperidin-4-yl-amine (1.28 g, 3.64 mmol) in CH2Cl2 (36 mL), stirred 15 minutes, cooled to 0° C., and treated with NaBH(OAc)3 (1.16 g, 5.46 mmol). The reaction was allowed to warm to RT as ice melted and stir 4 hours. The reaction was diluted with EtOAc (200 mL), washed with saturated bicarbonate solution, and brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 8% MeOH/CH2Cl2 to give 1.15 g (57%) of the desired product (Id).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][N:18]([CH2:25][C:26]3[CH:37]=[CH:36][C:29]([O:30][CH2:31][C:32]([O:34]C)=[O:33])=[CH:28][CH:27]=3)[C:19](=[O:24])[CH2:20][CH2:21][C:22]#[CH:23])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:25][C:26]3[CH:37]=[CH:36][C:29]([O:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:28][CH:27]=3)[C:19](=[O:24])[CH2:20][CH2:21][C:22]#[CH:23])=[CH:38][CH:39]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C#CCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)Cc1ccc(OCC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C#CCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)Cc1ccc(OCC(=O)O)cc1

Procedure:
The titled compound was prepared following the procedure F using methyl (4-{[{4-[(4-butylphenyl)ethynyl]benzyl}(pent-4-ynoyl)amino]methyl}phenoxy)acetate and NaOH 1N in the presence of MeOH/THF as a yellow oil (87%). 1H NMR (DMSO-d6, 300 MHz) δ 7.49 (m, 4H), 7.25-7.11 (m, 6H), 6.87 (m, 2H), 4.65 (s, 1H), 4.64 (s, 1H), 4.54 (s, 1H), 4.50 (s, 1H), 4.46 (s, 1H), 4.44 (s, 1H) 2.77-2.42 (m, 7H), 1.55 (m, 2H), 1.30 (m, 2H), 0.89 (t, J=7.3 Hz, 3H). M− (ESI): 506.4; M+ (ESI): 508.4. HPLC, Rt: 5.05 min (Purity: 99.1%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[NH:29][C:30](=[O:35])C(F)(F)F)=[N:4][C:5]([NH:8][C:9]2[CH:21]=[CH:20][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:42]([N:44](CC)[CH2:45]C)C.CN(C)C(Cl)=O>CO.ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[NH:29][C:30](=[O:35])[N:44]([CH3:45])[CH3:42])=[N:4][C:5]([NH:8][C:9]2[CH:21]=[CH:20][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: CCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NC(=O)C(F)(F)F)n3)cc2CC1
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NC(=O)N(C)C)n3)cc2CC1
Temperature: 45 °C
Reaction time: 84 h
Yield: 71.3 %

Procedure:
N-{(1R,2R)-2-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-2,2,2-trifluoro-acetamide (78 mg, 0.15 mmol) and Potassium carbonate (125 mg, 0.904 mmol) were combined in Methanol (10 mL), and were then heated at 45° C. After stirring 3.5 d, the reaction had reached ˜60% completion. After an additional 3 d, the mixture had evaporated to dryness, but the reaction had gone to completion as determined by HPLC of resolubilized material (DCM:MeOH). The mixture was reconcentrated to dryness after filtering off the solids. 1,4-Dioxane (5 mL) was added followed by Triethylamine (0.2 mL, 1.4 mmol) and N,N-Dimethylcarbamoyl chloride (21 uL, 0.23 mmol), and the reaction was stirred under an atmosphere of Nitrogen. After O.N. stirring, 0.5 mL DMF was added, and the mixture was sonicated to aid in solubilizing all the contents. After an additional 24 h, N,N-Dimethylcarbamoyl chloride (50 uL, 0.5 mmol) was added and stirring was continued. After 24 h, N,N-Dimethylcarbamoyl chloride (50 uL, 0.5 mmol) was added along with 3 mL dichloromethane to aid in solubility and to rinse the sidewalls of the flask. After 5 h, the contents were concentrated onto Celite and chromatographed on an ISCO column, eluting with 10% (5% NH4OH:MeOH):DCM. The product elutes at 10% polar solvent mix, and was collected and concentrated to afford 3-{(1R,2R)-2-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-1,1-dimethyl-urea (52 mg, 70%) as a yellow film. LCMS (m/e) 486 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.85 (s, 1H), 7.28 (m, 2H), 7.03 (m, 2H), 6.08 (d, 1H, J=7.1 Hz), 4.85 (d, 1H, J=7.2 Hz), 3.82 (m, 1H), 3.71 (m, 1H), 2.94 (m, 5H), 2.68 (s, 6H), 2.62 (m, 7H), 2.28 (m, 1H), 2.15 (m, 1H), 1.80 (m, 2H), 1.2-1.4 (m, 5H), 1.12 (t, 3H, J=7.1 Hz).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9].[CH3:18][Si](C=[N+]=[N-])(C)C>CO>[CH3:18][O:9][C:8](=[O:10])[C:7]1[CH:11]=[C:12]([O:16][CH3:17])[C:13]([O:14][CH3:15])=[C:5]([CH2:4][CH2:3][CH2:2][OH:1])[CH:6]=1
Reactant: COc1cc(C(=O)O)cc(CCCO)c1OC
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1cc(CCCO)c(OC)c(OC)c1
Reaction time: 0.17 h
Yield: 73.8 %

Procedure:
To a stirred solution of 3-(3-hydroxypropyl)-4,5-dimethoxybenzoic acid (Example 10, Step 1, 3.53 g, 14.7 mmol) in MeOH (37 mL) at 0° C. was slowly added trimethylsilyldiazomethane (TMSCHN2) (2.0 M, 37 mL, 73.5 mmol) over the course of 5 min. After stirring for 10 min the reaction mixture was concentrated. The crude product was purified by flash column chromatography on silica gel using 67% EtOAc in hexanes as an eluent to furnish 3-(3-hydroxypropyl)-4,5-dimethoxybenzoic acid methyl ester (2.76 g).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11](=[O:20])[C:10]([N:21]2[CH2:26][CH2:25][N:24](C(OCC)=O)[CH2:23][CH2:22]2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11](=[O:20])[C:10]([N:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCN(c2cn(Cc3ccccc3)c3cc(OC)ccc3c2=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(=O)c(N3CCNCC3)cn(Cc3ccccc3)c2c1

Procedure:
A mixture of the product of step iv) (1.8 g), ethanol (40 ml) and 20% w/v aqueous potassium hydroxide solution (40 ml) was heated to reflux overnight, cooled and evaporated to dryness. The residue was partitioned between water and dichloromethane and the organic layer was separated, washed with brine, dried (MgSO4) and evaporated to yield 1-benzyl-3-(piperazin-1-yl)-7-methoxy-4-quinolone (1.5 g) as a yellow foam: NMR (CDCl3) δ 2.80(1H,m), 3.20(8H,m), 3.73(3H,s), 5.28(2H,s), 6.59(1H,d), 6.88(1H,dd), 7.15(3H,m), 7.30(3H,m), 8.41(1H,d); m/Z 350 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([NH:14][CH2:15][CH3:16])=[C:12]([N:17]=O)[CH:11]=[N:10]1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([NH:14][CH2:15][CH3:16])=[C:12]([NH2:17])[CH:11]=[N:10]1
Reactant: [H][H]
Reactant: CCNc1c(N=O)cnn1-c1ccc(F)cc1F
Agent: [Pd]
Solvent: CO
Product: CCNc1c(N)cnn1-c1ccc(F)cc1F

Procedure:
A solution of 1-(2,4-difluorophenyl)-N-ethyl-4-nitroso-1H-pyrazol-5-amine (1.21 g, 5 mmol) in 20 mL of MeOH was hydrogenated for 3 h with hydrogen gas in a balloon in the presence of palladium (200 mg of the 10% wt. on activated carbon). The reaction mixture was filtered through a pad of celite washing with MeOH. The solvent was removed on the rotovap affording 1-(2,4-difluorophenyl)-N5-ethyl-1H-pyrazole-4,5-diamine as a bright orange viscous oil. This material was used without purification. MS (ES+): 224.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:3]=1.[C:13](OC(=O)C)(=[O:15])C>C(O)=O>[CH:13]([NH:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:3]=1)=[O:15]
Reactant: CC(=O)OC(C)=O
Reactant: NC1=NN(c2ccccn2)CC1
Solvent: O=CO
Product: O=CNC1=NN(c2ccccn2)CC1

Procedure:
3-Amino-1-(2-pyridyl)-2-pyrazoline (1.5 g) was added to formic acid (22 ml) at 60° in an atmosphere of nitrogen. The mixture was stirred whilst acetic anhydride (2.3 ml) was added dropwise. The mixture was heated at 100° for 1 hour before being evaporated in vacuo to give 3-formamido-1-(2-pyridyl)-2-pyrazoline which was recrystallised from isopropanol, m.p. 182°-183° (yield 1.17 g).
Reaction SMILES: [CH2:1]([C:4]1[O:8][C:7]([NH2:9])=[N:6][CH:5]=1)[CH2:2][CH3:3].[C:10]1([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:20]1([CH:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:17]([NH:9][C:7]2[O:8][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][N:6]=2)=[O:18])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCCc1cnc(N)o1
Product: CCCc1cnc(NC(=O)C(c2ccccc2)c2ccccc2)o1

Procedure:
The title compound, white solid, m.p. 122° C. and MS: m/e=320.2 (M+) was prepared in accordance with the general method of example 44a from 5-propyl-oxazol-2-ylamine and 2,2-diphenylacetic acid chloride.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[C:18]=4[CH3:24])=[N:15][N:14]=[C:13]([C:25]([O:27]C)=O)[C:9]=3[NH:10][C:11]=2[CH:12]=1)(=[O:3])[CH3:2].[NH3:29].CO>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[C:18]=4[CH3:24])=[N:15][N:14]=[C:13]([C:25]([NH2:29])=[O:27])[C:9]=3[NH:10][C:11]=2[CH:12]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1nnc(-c2cccc(N)c2C)c2c1[nH]c1cc(C(C)=O)ccc12
Reactant: N
Solvent: CO
Product: CC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)nnc(-c3cccc(N)c3C)c12
Temperature: 100 °C

Procedure:
A mixture of methyl 7-acetyl-1-(3-amino-2-methylphenyl)-5H-pyridazino[4,5-b]indole-4-carboxylate (0.520 g, 1.389 mmol) and ammonia in methanol (30 ml, 210 mmol) was heated in a sealed bottle at 100° C. for 2 hr. Removal of the volatiles under vacuum gave a crude product (0.501 g) as a tan solid. This crude was 82% pure, but was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]1C=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])C.[NH:12]1C2C=CC=CC=2N=C1CN(C1C2N=CC=CC=2CCC1)CC1C=CC(CN)=CC=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[OH:2][C:3]1[C:4]([CH:9]=[O:11])=[CH:5][CH:6]=[CH:7][N:12]=1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: COc1ccccc1C(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=Cc1cccnc1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 134.8 %

Procedure:
To a stirred solution of 1-(2-methoxy-phenyl)-ethanone (69 μL, 0.50 mmol), N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (200 mg, 0.50 mmol) and AcOH (0.10 mL, 1.4 mmol) in THF (5 mL) was added NaBH(OAc)3 and the mixture was stirred at room temperature for 48 hours. Purification of the crude light yellow foam to (267 mg) by column chromatography on silica gel (100:1:1-CH2Cl2:MeOH:NH4OH) followed by radial chromatography on silica gel (100:1:1-CH2Cl2:MeOH:NH4OH) afforded the desired product (83 mg, 27%) as a white foam.
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([CH:13]([CH3:15])[CH3:14])[C:11]2[N:10]=[C:9]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:26](O)=[O:27])=[C:21]4[C:25]=3[O:24][CH2:23][CH2:22]4)[N:8]=[CH:7][C:6]=2[N:5]([CH3:29])[C:4]1=[O:30])[CH3:2].F[B-](F)(F)F.[N:36]1(OC(N(C)C)=[N+](C)C)[C:40]2[CH:41]=[CH:42]C=[CH:44][C:39]=2N=N1.[CH:53]([N:56](C(C)C)CC)(C)C>ClCCl>[CH2:1]([C@H:3]1[N:12]([CH:13]([CH3:15])[CH3:14])[C:11]2[N:10]=[C:9]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:26]([NH:36][CH:40]4[CH2:39][CH2:44][N:56]([CH3:53])[CH2:42][CH2:41]4)=[O:27])=[C:21]4[C:25]=3[O:24][CH2:23][CH2:22]4)[N:8]=[CH:7][C:6]=2[N:5]([CH3:29])[C:4]1=[O:30])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C(C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC4CCN(C)CC4)c4c3OCC4)nc2N1C(C)C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
7-[[(7R)-7-Ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 22f (120 mg, 0.29 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (93 mg, 0.29 mmol) were dissolved in 30 mL of dichloromethane followed by addition of diisopropylethylamine (83 mg, 0.64 mmol) and 1-methyl-piperidyl-4-yl amine (33 mg, 0.29 mmol) successively. The reaction solution was stirred for 3 hours. The resulting solution was washed with saturated sodium carbonate solution (30 mL) and saturated sodium chloride solution (30 mL) successively. The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-(1-methyl-4-piperidyl)-2,3-dihydrobenzofuran-4-carboxamide 22 (117 mg, yield: 80.0%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9](P(OCC)(OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].C=O.[C:25](=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[CH2:25])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(Cc1ccccc1Cl)P(=O)(OCC)OCC
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: O
Product: C=C(Cc1ccccc1Cl)C(=O)OCC
Temperature: 90 °C
Reaction time: 6 h
Yield: 69.8 %

Procedure:
To a stirred mixture of ethyl 3-(2-chlorophenyl)-2-(diethoxyphosphoryl)propanoate (step 1, 14.6 g, 41.9 mmol) and 37% formaldehyde in water (20 mL) was added a solution of potassium carbonate (17.4 g) in water (80 mL) at the room temperature and the mixture was stirred for 6 h at 90° C. After cooling to room temperature, the mixture was extracted with diethyl ether (300 mL), and then the organic layer washed with brine (100 mL), dried over magnesium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (300 g) eluting with hexane/ethyl acetate (30/1) to afford 6.57 g (70%) of the title compound as a colorless oil:
Reaction SMILES: [C:1]([O:20][CH:21]1[CH2:26][CH2:25][N:24]([OH:27])[CH2:23][CH2:22]1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[CH:35]=[CH2:36]>C(O)C>[C:1]([O:20][CH:21]1[CH2:26][CH2:25][N:24]([O:27][CH2:36][CH:35]=[CH2:34])[CH2:23][CH2:22]1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC1CCN(O)CC1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=CCON1CCC(OC(=O)CCCCCCCCCCCCCCCCC)CC1

Procedure:
Repeating the general procedure of Example 1 using 1-hydroxy-piperdin-4-yl stearate, potassium carbonate and allyl bromide in ethanol solvent yields the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CCCC)CCCC)CCC.O>CC(C)=O>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:6][CH:7]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Solvent: CC(C)=O
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: N#CC=CS(=O)(=O)c1ccc(NS(=O)(=O)c2ccc(F)cc2)cc1
Reaction time: 8 h

Procedure:
24 g (0.12 mol) of 3-(4-aminobenzenesulfonyl)acrylonitrile are dissolved in 200 ml acetone. 23.4 g (0.12 mol) of a solution of p-fluorobenzenesulfonyl chloride in 100 ml acetone are added thereto in several portions at room temperature, followed by 28 ml (0.12 mol) tributylamine. After standing for 8 hours at room temperature the reaction mixture is poured into 1 liter of water to separate the reaction product, which is then taken up in chloroform, and treated as described hereinabove to give 3-[4-(4-fluorobenzenesulfonamido)benzenesulfonyl]acrylonitrile: ##SPC21##
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][O:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>C1COCC1.CCOC(C)=O>[CH3:34][O:35][CH:36]1[CH2:41][CH2:40][N:39]([S:20]([C:16]2[CH:15]=[C:14]([C:10]3[N:9]=[C:8]([C:6]4[CH:5]=[C:4]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=5)[CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:13]=[CH:12][CH:11]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:21])=[O:22])[CH2:38][CH2:37]1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: COC1CCNCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC1CCN(S(=O)(=O)c2cccc(-c3cccc(-c4cc(-c5ccc(C(F)(F)F)cc5)cc(C)n4)n3)c2)CC1
Yield: 38.8 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available 4-methoxypiperidine [CAS-no. 4045-24-3] (0.236 g, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.090 g, 39%) as a white foam. MS (ISP) 568.3 [(M+H)+]; mp 107° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Br:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30]>>[Br:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)=[O:30]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1ccccc1Br
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4Br)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP3 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2-bromobenzoic acid as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.