Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[N:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[C:4](=[O:13])[CH2:3]1.[BH4-].[Na+].O.[NH4+].[Cl-]>CO>[C:9]([O:8][C:6](=[O:7])[NH:5][C:2]([CH3:14])([CH3:1])[CH2:3][CH2:4][OH:13])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC1(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC(C)(CCO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
4,4-Dimethyl-1-tert-butyloxycarbonyl-azetidine-2-one (32.5 g, synthesized according to Schoen et al., J. Med. Chem. 1994, 37 (7), 897) was dissolved in methanol (450 ml). The solution was cooled to 0° by means of an ice bath and treated with sodium borohydride (18.3 g, 6 portions over 45 minutes). The mixture was allowed to stir for 3 hours at 0°, warmed to room temperature and stirred for another 60 min. The reaction mixture was then poured into a mixture of ice, water and sat. NH4Cl solution and extracted with ether. The organic layer was separated, washed with brine, dried over Na2SO4 and evaporated. The residual oil was purified by flash chromatography (gradient of hexanes in ethyl acetate: 7/3 to 1/1). The fractions containing the product were combined, evaporated and dried in vacuo to leave a colorless oil (26.7 g).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][OH:33])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][OH:33])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCO)c4ccc(OC(F)F)cc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CCCO)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.7 %

Procedure:
To a pale yellow solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-hydroxypropyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (17 mg, 28.9 μmol) in dichloromethane (4.00 mL) was added TFA (1480 mg, 1.0 mL, Eq 450), the reaction mixture turned orange and was stirred at 25° C. for 24 h, mixture concentrated and the residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 1 h, then evaporated to an off-white solid, which was dissolved in dichloromethane and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane and cyclohexane added to allow solid formation, light yellow solid was separated by filtration and dried under high vacuum to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-hydroxypropyl)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (12 mg, 26.2 μmol, 90.6%). MS (M+H)+=459; 1H NMR (DMSO-d6) δ: 9.05 (s, 1H), 8.37 (s, 1H), 8.19 (s, 1H), 7.79-7.94 (m, 2H), 7.38 (d, J=8.7 Hz, 1H), 7.18 (t, J=74.4 Hz, 1H), 4.62-4.68 (m, 1H), 4.59 (t, J=6.8 Hz, 2H), 3.40-3.51 (m, 2H), 2.06 (t, J=6.2 Hz, 1H), 1.49 (s, 9H).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:12][CH:11]([OH:13])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Si:1]([O:8][CH:9]1[CH2:12][C:11](=[O:13])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CC(O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CC(=O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3-(tert-butyldimethylsilyloxy)cyclobutanol (2.59 g, 13 mmol), sodium bicarbonate (3 ml, 38 mmol), and Reactant 1[?] (7 g, 15 mmol) in DCM (40 ml) was stirred at RT in 4 h, the solid was filtered; the filtrated was purified by ISCO (5% EtOAc/Hexanes) to give the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][CH3:28])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[C:29]([O:32][CH2:33][C:34]([CH3:46])([CH3:45])[O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:31])[CH3:30].C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:29]([O:32][CH2:33][C:34]([O:35][C:36]1[CH:37]=[CH:38][C:39]([N:8]2[C:9](=[O:26])[C:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]#[N:25])=[CH:14][CH:13]=3)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]2[CH2:27][CH3:28])=[CH:40][CH:41]=1)([CH3:46])[CH3:45])(=[O:31])[CH3:30]
Reactant: CCCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(=O)OCC(C)(C)Oc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCc1nc(CC)n(-c2ccc(OC(C)(C)COC(C)=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 77.2 %

Procedure:
To a suspension of 4′-[(4-butyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.5 g), {4-[2-(acetyloxy)-1,1-dimethylethoxy]phenyl}boronic acid (0.68 g), triethylamine (0.96 mL), pyridine (0.56 mL) and molecular sieves 4 A (1 g) in dichloromethane (10 mL) was added copper(II) acetate (0.68 g) and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.6 g, 76%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:14][CH:13]=1)[CH:8]=[N:7]2.[F:25][C:26]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([F:48])[C:27]=1[CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[F:48][C:35]1[CH:36]=[C:37]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]4[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]4)=[CH:14][CH:13]=2)[CH:8]=[N:7]3)[CH:38]=[C:26]([F:25])[C:27]=1[CH2:28][N:29]1[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1
Reactant: CN1CCN(c2ccc(-c3cnc4cccc(Br)c4n3)cc2)CC1
Reactant: CC1(C)OB(c2cc(F)c(CN3CCOCC3)c(F)c2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: CN1CCN(c2ccc(-c3cnc4cccc(-c5cc(F)c(CN6CCOCC6)c(F)c5)c4n3)cc2)CC1
Temperature: 105 °C

Procedure:
A microwave tube is charged with 8-Bromo-2-[4-(4-methyl-piperazin-1-yl)-phenyl]-quinoxaline (2.6 g, 6.783 mmol), 4-[2,6-Difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-morpholine (Step 87.1, 2.68 g, 7.12 mmol), S-Phos (258 mg, 0.611 mmol), K3PO4 (4.41 g, 20.4 mmol) and Pd(OAc)2 (45.68 mg, 0.203 mmol). After several cycles of vacuum/purge with argon, a mixture of 370 μl deionized water in 30 ml 1,2-dimethoxy-ethane is added. The reaction mixture is then heated to 105° C. for 12 h. After cooling, the reaction mixture is diluted with CH2Cl2, poured onto a saturated solution of NaHCO3 and extracted 3× with CH2Cl2. The combined organic layers are washed with water, brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, CH2Cl2/CH2Cl2:EtOH:NH3 90:9:1 4:6) to afford the title compound as yellow solid, Rt=0.742 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 516 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32](Cl)[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:16]=[C:17]([F:24])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:24][C:17]1[CH:16]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:14]=[C:13]([F:12])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2ccc(Cl)c(Cl)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 29.8 %

Procedure:
3,4-Dichlorobenzeneboronic acid (49.6 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (19 mg, 30%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [N+]([O-])(O)=O.[F:5][C:6]([F:21])([O:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([NH2:20])=[NH:19])[CH:14]=[CH:15][CH:16]=1)[CH:7]([F:9])[F:8].CN(C)[CH:24]=[CH:25][C:26]([C:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=1)=O.[OH-].[Na+]>C(O)CC>[F:5][C:6]([F:21])([O:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2[N:20]=[C:26]([C:28]3[CH:29]=[C:30]([O:38][CH3:39])[C:31]([O:36][CH3:37])=[C:32]([O:34][CH3:35])[CH:33]=3)[CH:25]=[CH:24][N:19]=2)[CH:14]=[CH:15][CH:16]=1)[CH:7]([F:8])[F:9]
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Reactant: COc1cc(C(=O)C=CN(C)C)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: O=[N+]([O-])O
Product: COc1cc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
1189.4 mg (0.75 mmol) of 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrate are added to a solution of 200 mg (0.75 mmol) of 3-dimethylamino-1-(3,4,5-trimethoxy-phenyl)-2-propen-1-one in 11.5 ml of 1-propanol. After the addition of 33.2 mg (0.83 mmol) of sodium hydroxide, the reaction mixture is boiled under reflux for 23 hours. After cooling to RT, the reaction product is isolated by filtration and washed with 1-propanol and water. After drying at 60° C. under HV, N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3,4,5-trimethoxyphenyl)-2-pyrimidineamine is obtained; Rf =0.75 (methylene chloride:methanol=9:1), FAB-MS: 454 (M+ +1), m.p. 132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=1)=[O:8].C([BH3-])#N.[Na+].[CH3:30][C:31]([CH3:33])=O>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([CH:31]([CH3:33])[CH3:30])[CH2:24][CH2:25]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(F)cn1)c1cc(Cl)ccc1NCC1CCNCC1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CCC(CNc2ccc(Cl)cc2C(=O)Nc2ccc(F)cn2)CC1
Temperature: 50 °C
Reaction time: 24 h
Yield: 21 %

Procedure:
A solution of 5-chloro-N-(5-fluoropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 218 (0.50 g, 1.37 mmol) in 10 mL of acetone and 6 mL of 95:5 methanol-acetic acid was treated with sodium cyanoborohydride (0.35 g, 5.5 mmol). After stirring at 50° C. for 24 h, the solution was concentrated in vacuo; and the residue was subjected to silica gel chromatography. Elution with 98:2 dichloromethane-methanol furnished the title compound (0.12 g, 21%) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]1([C:7]2[N:8]([CH2:19][C:20]3[CH:39]=[CH:38][C:23]([CH2:24][O:25][C:26]4[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(OCc2ccc(Cn3c(-c4ccccc4)cc4ccccc43)cc2)cc1
Temperature: 0 °C
Yield: 45.8 %

Procedure:
To a solution of 2-phenylindole (0.17 g, 0.86 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 35 mg, 0.86 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 10 min. Methyl 3-(4-{[4-(chloromethyl)benzyl]oxy}phenyl)propanoate (0.25 g, 0.78 mmol) was added to the obtained mixture and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, and the mixture washed with 5% aqueous potassium hydrogensulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=3/1) to give the title compound (0.17 g, yield 46%) as a colorless oil. 1H NMR (CDCl3) δ: 2.59 (2H, t, J=7.8 Hz), 2.89 (2H, t, J=7.8 Hz), 3.66 (3H, s), 4.98 (2H, s), 5.38 (2H, s), 6.66 (1H, s), 6.88 (2H, d, J=8.7 Hz), 7.00-7.20 (7H, m), 7.29-7.47 (7H, m), 7.67 (1H, m).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[O:20])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:21]([O:29][CH2:30][CH3:31])(=[O:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[O:20])[CH2:12][CH:13]([CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:21]([O:29][CH2:30][CH3:31])=[O:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(C=Cc1ccccc1)c1ccc2ccccc2c1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc2ccccc2c1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(2-naphthalenyl)-3-phenylprop-2-en-1-one and diethyl malonate, diethyl 2-[3-(2-naphthalenyl)-3-oxo-1-phenylpropyl]malonate was obtained as colourless solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([C:9]1[CH:10]=[CH:11][C:12](=O)[NH:13][N:14]=1)[CH2:7][CH3:8].[OH-].[Na+].C(=O)([O-])O.[Na+]>O>[Cl:3][C:12]1[N:13]=[N:14][C:9]([CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=1
Reactant: CCCc1ccc(=O)[nH]n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCc1ccc(Cl)nn1
Temperature: 100 °C
Yield: 73.2 %

Procedure:
46.0 g of phosphorus oxychloride were heated to 60° C. in a sulphonation flask under nitrogen and treated within 1 hour with 27.6 g of 6-propyl-3(2H)-pyridazinone (prepared according to Example 3) in small portions. The mixture was subsequently heated slowly to 100° C. and stirred at this temperature until the reaction was complete according to thin-layer chromatography (about 2 hours). After cooling to room temperature, the dark brown solution was poured into 1 l of water and neutralized with solid sodium hydroxide and sodium hydrogen carbonate. The aqueous phase was subsequently extracted once with 500 ml of tert.butyl methyl ether and then twice with 250 ml of tert.butyl methyl ether each time. The organic phases were washed with 500 ml of water and the aqueous phase was back-extracted twice with 100 ml of tert.butyl methyl ether each time. The combined organic phases were dried over sodium sulphate and freed from solvent on a rotary evaporator. Distillation of the resulting dark brown oil in a high vacuum gave in the main run 22.9 g (73.1%) of 3-chloro-6-propylpyridazine as a colourless liquid; b.p. 72°-74° C./0.4 Torr.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([CH2:37][CH2:38][CH3:39])[N:11]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]4[NH:36][N:35]=[N:34][N:33]=4)=[CH:22][CH:21]=3)[C:12]=2/[CH:13]=[CH:14]/[C:15]([O:17]C)=[O:16])[C:4]([CH3:7])=[CH:5][CH:6]=1.C[Si](C)(C)[O-].[K+]>C1COCC1>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([CH2:37][CH2:38][CH3:39])[N:11]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]4[NH:33][N:34]=[N:35][N:36]=4)=[CH:22][CH:21]=3)[C:12]=2/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: CCCc1nc(-n2c(C)ccc2C)c(/C=C/C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCc1nc(-n2c(C)ccc2C)c(/C=C/C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 85.4 %

Procedure:
A solution of methyl (E)-3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-propyl-1-[[2'-(1H-tetrazol-5-yl) 1,1'-biphenyl-4-yl]methyl]-1H-imidazol-5-yl]-2-propenoate (Example 52, 1.55 g, 3 mmol), and potassium trimethylsilanolate (0.96 g, 7.5 mmol) in dry THF (80 mL) was stirred at room temperature for 3 hours under an atmosphere of dry nitrogen. The resulting precipitate was collected by filtration, air dried, and then dissolved in water (50 mL). The free acid was precipitated out by the addition of 1N HCl and collected by filtration giving (E)-3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-propyl-1-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-yl]methyl]-1H-imidazol-5-yl]-2-propenoic acid (1.3 g, 83%) as a partial hydrate, mp 144 150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17](=[O:34])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[F:35][C:36]([F:41])([F:40])[C:37](O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([N:21]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:37][C:36]([F:41])([F:40])[F:35])[C:17](=[O:34])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)C(F)(F)F
Reactant: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1NC1CCN(c2ccncc2)CC1
Product: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1N(CC(F)(F)F)C1CCN(c2ccncc2)CC1

Procedure:
Similarly to Method B in Example 43 and using 4-(6-chloronaphthalene-2-sulfonyl)-1-[1-(4-pyridyl)-4-piperidinylamino}-2-piperazinone (200 mg) and trifluoroacetic acid (5 ml) instead of acetic acid, the title compound (37 mg) was obtained as colorless crystals.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:24]2=[N:25][CH:26]=[N:27][C:28]([O:29][C@H:30]3[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[C:31]3=[O:39])=[C:23]2[CH:22]=[N:21]1>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:24]2=[N:25][CH:26]=[N:27][C:28]([O:29][C@@H:30]([CH2:34][CH2:33][NH:32][S:35]([CH3:38])(=[O:37])=[O:36])[C:31]([NH:12][C:9]3[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=3)=[O:39])=[C:23]2[CH:22]=[N:21]1
Reactant: CS(=O)(=O)N1CC[C@H](Oc2ncnc3c2cnn3-c2ccccc2Cl)C1=O
Reactant: Cc1ccc(N)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)[C@H](CCNS(C)(=O)=O)Oc2ncnc3c2cnn3-c2ccccc2Cl)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 36 %

Procedure:
Trimethylaluminium (2M in hexane) (0.164 mL, 0.33 mmol) was added to 5-methylpyridin-2-amine (33.8 mg, 0.31 mmol) in toluene (5 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (3S)-3-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-1-(methylsulfonyl)pyrrolidin-2-one (Intermediate AC1) (116 mg, 0.28 mmol) in toluene (1 mL) was added and the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was then heated to reflux for 2.5 hours. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was neutralised with citric acid and sodium potassium tartrate solution (sat.) and stirred vigorously for 45 mins. The mixture was separated and the aqueous re-extracted with ethyl acetate, the organic layer was dried (MgSO4) and evaporated. The residue was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents to afford the product (52.0 mg, 35.4%). 1H NMR (400 MHz, CDCl3) δ 2.30 (3H, s), 2.37-2.55 (2H, m), 2.98 (3H, s), 3.35-3.55 (2H, m), 4.95-5.10 (1H, m), 6.04 (1H, t), 7.44-7.58 (4H, m), 7.60-7.65 (1H, m), 8.07-8.15 (2H, m), 8.44 (1H, s), 8.61 (1H, s), 8.69 (1H, s); m/z (ES+) (M+H)+=516.28; HPLC tR=1.84 min.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[N:7][CH:6]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[NH2:11][C:8]1[N:7]=[CH:6][C:5]([CH2:4][OH:3])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc(N)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(CO)cn1
Reaction time: 1.5 h
Yield: 69.2 %

Procedure:
To a solution of 6-aminonicotinic acid ethyl ester (1.18 g, 7.1 mmol) in anhydrous THF (24 mL) was added a solution of lithium aluminum hydride (0.41 g, 10.6 mmol) in THF (12 mL) at 0° C. over 10 min and the mixture stirred for 1.5 h. To the reaction was added sequentially 0.5 mL H2O, 0.5 mL 15% aqueous NaOH and 1.5 mL H2O and the resultant slurry was filtered. The filtrate was dried (MgSO4), filtered, concentrated and purified by column chromatography (10% MeOH/CH2Cl2) to give 6-amino-3-hydroxymethylpyridine (0.61 g, 69%) as colorless crystals. 1H NMR (MeOD) δ 3.31 (s, 1H (OH)), 4.43 (s, 2H), 6.58 (d, 1H, J=8.4 Hz), 7.48 (d, 1H, J=8.7 Hz), 7.85 (s, 1H).
Reaction SMILES: [F:1][C:2]1([F:19])[C:5]2([CH2:9][CH2:8][N:7]([C:10]3[C:11]4[CH:18]=[CH:17][NH:16][C:12]=4[N:13]=[CH:14][N:15]=3)[CH2:6]2)[NH:4][CH2:3]1.CC1N([C:26]([CH2:28][C:29]#[N:30])=[O:27])N=C(C)C=1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>O1CCOCC1>[F:19][C:2]1([F:1])[C:5]2([CH2:9][CH2:8][N:7]([C:10]3[C:11]4[CH:18]=[CH:17][NH:16][C:12]=4[N:13]=[CH:14][N:15]=3)[CH2:6]2)[N:4]([C:26](=[O:27])[CH2:28][C:29]#[N:30])[CH2:3]1
Reactant: FC1(F)CNC12CCN(c1ncnc3[nH]ccc13)C2
Reactant: Cc1cc(C)n(C(=O)CC#N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#CCC(=O)N1CC(F)(F)C12CCN(c1ncnc3[nH]ccc13)C2
Temperature: 100 °C
Reaction time: 1.25 h
Yield: 83.1 %

Procedure:
An optically-active compound of 4-(3,3-difluoro-1,6-diazaspiro[3,4]oct-6-yl)-7H-pyrrolo[2,3-d]pyrimidine (170 mg) was mixed with 1-cyanoacetyl-3,5-dimethylpyrazole (209 mg), N,N-diisopropylethylamine (117 μl) and 1,4-dioxane (3.4 ml), and the mixture was stirred at 100° C. for 75 minutes. The mixture was cooled to room temperature. Thereto was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted with ethyl acetate twice again. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/ethyl acetate=2/1, followed by chloroform/methanol=92/8 to 3/1). The mixture was concentrated under reduced pressure, and the resulting residue was slurry-washed with a mixed solvent of n-heptane/ethanol (3/1) to give the titled compound (177 mg).