Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[C:16](F)[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@@H:32]([CH2:39][CH3:40])[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CCCCO.CS(C)=O>[CH2:1]([NH:8][C:9]1[N:17]=[C:16]([NH:31][C@@H:32]([CH2:39][CH3:40])[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](N)C(O)C(C)(C)C
Reactant: CC(C)n1cnc2c(NCc3ccccc3)nc(F)nc21
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC[C@H](Nc1nc(NCc2ccccc2)c2ncn(C(C)C)c2n1)C(O)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of benzyl-(2-fluoro-9-isopropyl-9H-purin-6-yl)-amine (40 mg, 1 eq, 0,14 mmol) in n-BuOH/DMSO (5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.12 mL, 4.9 eq, 0.69 mmol) followed by (3RS,4S)-4-amino-2,2-dimethyl-hexan-3-ol (57 mg, 2.8 eq, 0.39 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×50 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with hexane:ether:MeOH (50:50:0→50:50:2) to afford the title compound as a white solid; Yield: 7.2 mg (13%). (53% de 4S,3R: 47% de 4S,3S). 1H-NMR (d-CDCl3, 250 MHz): δ 0.99-1.04 (m, 12H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 1.56+1.58 (2×d, 6H, J=6.63+6.79 Hz, —CH(CH3)2), 1.64-1.87 (m, 2H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.57 (d, 1H, J=1.42 Hz, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.73-3.86 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 4.57-4.69 (m, 1H, —CH(CH3)2), 4.78-4.86 (m, 2H, —HNCH2-Bz), 5.22-5.34+5.95-6.08 (2×m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 7.26-7.44 (m, 6H, 5×Bz-H+HNCH2-Bz), 7.53 (s, 1H, —N═CH—N). FABMS m/z (relative intensity): 411 ([M+H]+, 85), 323 (100). Accurate Mass (N+H): Actual: 411.2872, Measured: 411.2860.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][O:7][C:8]2[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=2[CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.Br[CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)(O)[O-].[Na+].O>C(#N)C>[Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][O:7][C:8]2[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=2[CH2:10][CH2:11][N:12]([CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCCBr
Reactant: COC(=O)c1ccc(CNCCc2ccccc2OCc2ccc(Br)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CCCCN(CCc1ccccc1OCc1ccc(Br)cc1)Cc1ccc(C(=O)OC)cc1

Procedure:
5.00 g (11.0 mmol) of methyl 4-[({2-[(4-bromobenzyl)oxy]phenethyl}amino)-methyl]benzoate from Ex. VIII, 2.30 g (11.0 mmol) of ethyl 5-bromovalerate and 1.109 g (13.21 mmol) of sodium bicarbonate in 30 ml of acetonitrile are heated at reflux for 18 hours. The reaction mixture is admixed with water and extracted with methylene chloride. The organic phase is washed with saturated sodium chloride solution and dried over magnesium sulphate and the solvent is distilled off under reduced pressure. The residue is purified by chromatography over silica gel using the mobile phase methylene chloride/methanol 100/1.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH2:20])[C:18](=[O:21])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1.CN(C)C1C=CC=CC=1.C[Si](Cl)(C)C.[CH:36]([NH:38][C:39]1[S:40][CH:41]=[C:42]([C:44](=[O:48])[C:45](O)=[O:46])[N:43]=1)=[O:37].S(Cl)(Cl)=O>C(Cl)Cl.O.CN(C)C=O.C(N(CC)CC)C>[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:45](=[O:46])[C:44]([C:42]4[N:43]=[C:39]([NH:38][CH:36]=[O:37])[S:40][CH:41]=4)=[O:48])[C:18](=[O:21])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Agent: C[Si](C)(C)Cl
Agent: O=CN=c1[nH]c(C(=O)C(=O)O)cs1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(NC=O)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-amino-3-cephem-4-carboxylic acid (1.46 g.), triethylamine (0.9292 g.) and dimethylaniline (0.713 g.) in methylene chloride (30 ml.) was stirred for 20 minutes at room temperature. To the mixture was added a solution of trimethylsilyl chloride (1.043 g.) in methylene chloride (10 ml.) over 5 minutes under ice-cooling, and the mixture was stirred for 2 hours at room temperature and then cooled to -25° C. On the other hand, a suspension of 2-(2-formylamino-1,3-thiazol-4-yl)glyoxylic acid, which can be represented as 2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylic acid, (0.96 g.), thionyl chloride (0.697 g.) and dimethylformamide (0.214 g.) in methylene chloride (12 ml.) was stirred for 4 hours, and the mixture was added to the above obtained cooled mixture over 12 minutes at -25° to -20° C. The mixture was further stirred for 30 minutes at the same temperature and for 30 minutes at -20° to -10° C. After the reaction, the reaction mixture was added to water (100 ml.), and stirred for 30 minutes at room temperature. The white precipitates were collected by filtration and then dried to give dark brown powder of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-formylamino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH2:13]([N:20]1[C:24]([CH:25]=[O:26])=[CH:23][N:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:13]([N:20]1[C:24]([CH:25]([OH:26])[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)=[CH:23][N:22]=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Fc1ccc(CCCBr)cc1
Reactant: O=Cc1cncn1Cc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(CCCc1ccc(F)cc1)c1cncn1Cc1ccccc1
Temperature: 25 °C
Yield: 86 %

Procedure:
5,4 g of magnesium turnings are covered with 50 ml of dry tetrahydrofuran. A solution of 1-bromo-3-(4-fluorophenyl)propane (48,7 g) in 200 ml of dry tetrahydrofuran is then added dropwise to the mixture at such a rate that a smooth reaction is maintained. After the addition is complete, the reaction mixture is refluxed for one additional hour and cooled to room temperature. To the reaction mixture is then added dropwise the solution of 1-benzyl-5-imidazolecarbaldehyde (20,9 g) in 200 ml of tetrahydrofuran. After the addition is complete, the reaction mixture is refluxed for 2 hours, cooled and poured into cold saturated ammonium chloride solution. Tetrahydrofuran phase is removed and the water phase is extracted three times with ethyl acetate. Organic phases are combined, dried and evaporated to dryness. The residue is suspended with diethyl ether and filtered. Yield 86%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:6]2[NH:7][C:8](=[O:18])[CH2:9][N:10]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:11][C:5]=2[CH:4]=1.[F-].[Cs+].[CH2:26](Br)[CH3:27].C(#N)C>[I-].[Na+]>[CH2:26]([N:7]1[C:6]2[CH:19]=[C:20]([N+:21]([O-:23])=[O:22])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH2:11][N:10]([C:12](=[O:17])[C:13]([F:14])([F:15])[F:16])[CH2:9][C:8]1=[O:18])[CH3:27]
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CN(C(=O)C(F)(F)F)C2
Reactant: CCBr
Agent: [Cs+]
Agent: [F-]
Agent: [I-]
Solvent: CC#N
Product: CCN1C(=O)CN(C(=O)C(F)(F)F)Cc2cc(OC)c([N+](=O)[O-])cc21
Temperature: 45 °C
Yield: 85.1 %

Procedure:
A mixture of 7-Methoxy-8-nitro-4-(2,2,2-trifluoro-acetyl)-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.640 g, 0.00192 mol), Cesium fluoride (0.580 g, 0.00382 mol), Ethyl bromide (0.860 mL, 0.0116 mol) and Sodium iodide (0.0014 g, 0.0000093 mol) in Acetonitrile (15.0 mL, 0.287 mol) was heated at 45° C. for 8 hr. The reaction was evaporated, taken up in DCM/water, separated, washed, dried and evaporated to give 1-Ethyl-7-methoxy-8-nitro-4-(2,2,2-trifluoro-acetyl)-1,3,4,5-tetrahydro-benzo[e][1,4]diazepinone as a solid (0.59 g, 85%). Mp 128-129° C.; LCMS (m/e) 362 (M+1); 1H-NMR (DSMO, 400 MHz) δ 8.07 (d, 1H), 7.95 (s, 0.5H), 7.67 (s, 1H), 7.53 (s, 0.5H), 4.69 (s, 1H), 4.06 (s, 0.5H), 4.00 (s, 1H), 3.95 (s, 1H), 3.91-89 (q, 2H), 1.08-04 (t, 3H).
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].[Br:13][C:14]1[CH:15]=[C:16]([C:26]2[O:31][C:30](=[O:32])[C:29]3[CH:33]=[C:34]([Cl:38])[CH:35]=[C:36]([CH3:37])[C:28]=3[N:27]=2)[N:17]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1>O.CN(C)C=O>[Br:13][C:14]1[CH:15]=[C:16]([C:26]([NH:27][C:28]2[C:36]([CH3:37])=[CH:35][C:34]([Cl:38])=[CH:33][C:29]=2[C:30]([N:4]([CH3:3])[NH:5][CH3:6])=[O:32])=[O:31])[N:17]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)cn3-c3ncccc3Cl)nc12
Reactant: CNNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNN(C)C(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(Br)cn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 23.3 %

Procedure:
To a mixture of 0.29 g of N,N′-dimethylhydrazine dihydrochloride, 1 ml of water, 0.31 g of potassium carbonate and 10 ml of N,N-dimethylformamide was added 1.0 g of 2-[4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrol-2-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-one. The resulting mixture was stirred at room temperature for 6 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.26 g of 4-bromo-N-[4-chloro-2-(N,N′-dimethylhydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxamide of the formula:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=2)([C:9]2[CH:13]=[C:12]([C:14](=[O:17])[CH2:15][CH3:16])[NH:11][CH:10]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:32][CH2:33][CH3:34]>CN(C=O)C>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=2)([C:9]2[CH:13]=[C:12]([C:14](=[O:17])[CH2:15][CH3:16])[N:11]([CH2:32][CH2:33][CH3:34])[CH:10]=2)[N:3]=1
Reactant: CCC(=O)c1cc(C2(c3cccc(Br)c3)N=C(N)N(C)C2=O)c[nH]1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCn1cc(C2(c3cccc(Br)c3)N=C(N)N(C)C2=O)cc1C(=O)CC
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.7 %

Procedure:
Under a nitrogen atmosphere, to a solution of 2-amino-5-(3-bromo-phenyl)-3-methyl-5-(5-propionyl-1H-pyrrol-3-yl)-3,5-dihydro-imidazol-4-one (0.2 g, 0.51 mmol) in DMF (5 mL) was added Cs2CO3 (0.33 g, 1.02 mmol) and iodopropane (0.12 g, 0.70 mmol). The reaction mixture was sealed and stirred at room temperature for 20 hours. DMF was removed in vacuo, the residue was taken back CHCl3 and filtered. Evaporation and purification by combi flash chromatography (methylene chloride/methyl alcohol/triethyl amine, 9.5/0.4/0.1) gave the title compound as a white solid (0.16 g, 72% yield), mp 260° C., 1H NMR (400 MHZ, CDCl3) δ 0.73 (t, 3H), 1.01 (t, 3H), 1.03 (q, 2H), 2.66 (m, 2H), 2.91 (s, 3H), 4.12 (q, 2H), 6.6 (bs, 2H), 6.87 (s, 1H), 6.98 (s, 1H), 7.23 (m, 1H), 7.37 (m, 1H), 7.45 (m, 1H), 7.57 (m, 1H), MS m/e (M−H)− 429.1.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[CH2:18][CH:19]([OH:22])CO)=[CH:15][C:14]([O:23][CH3:24])=[CH:13][CH:12]=2>O.CC(C)=O>[Cl:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[CH2:18][CH:19]=[O:22])=[CH:15][C:14]([O:23][CH3:24])=[CH:13][CH:12]=2
Reactant: COc1ccc2ncc(Cl)c(CC(O)CO)c2c1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc2ncc(Cl)c(CC=O)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
A solution of sodium periodate (2.88 g, 13.5 mmol, 1.2 eq) in water (30 mL) is added dropwise at 0° C. to a stirred solution of 3-(3-chloro-6-methoxy-quinolin-4-yl)-propane-1,2-diol (3.0 g, 11.2 mmol, 1.0 eq) in acetone (50 mL) and water (20 mL). After 30 minutes stirring at 0° C. the reaction mixture is extracted with ethyl acetate (3×100 mL) and water (100 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to afford (3-chloro-6-methoxy-quinolin-4-yl)-acetaldehyde as a light brown solid (2.6 g, 99% yield).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:21][C:22](=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1COCC1.O>[O:29]=[C:22]([CH:21]=[P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
triphenylphosphine (30.0 g, 114.3 mmol) is added, at ambient temperature, to a solution of commercial ethyl 4-chloro-3-oxobutanoate (18.81 g, 114.3 mmol) in 200 mL of anhydrous THF. The reaction medium is taken to reflux for 18 h before being concentrated under vacuum. The oil obtained is taken up in distilled water then washed with ether. The aqueous phase is then basified by a saturated aqueous solution of NaHCO3 (up to pH 8). After extraction with AcOEt, the organic phases are combined, dried over MgSO4, filtered then concentrated under vacuum. Purification is carried out by recrystallization from ether in order to produce, after filtration and drying, compound 5′-2 (14.96 g, 38.0 mmol, 34%) in the form of a slightly yellow solid.
Reaction SMILES: O.[NH:2]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3]1.C(Cl)(=O)C(Cl)=O.[Br:16][C:17]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:18]=1[O:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[N:28]O)[NH2:27])[CH2:22][CH2:21]1.C(N(CC)CC)C.[H-].[Na+]>C1COCC1.CN(C=O)C>[Br:16][C:17]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:18]=1[O:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[N:27]=[C:7]([C:4]3[CH:5]=[CH:6][NH:2][CH:3]=3)[O:9][N:28]=2)[CH2:22][CH2:21]1
Reactant: NC(=NO)N1CCC(Oc2cc(F)ccc2Br)CC1
Reactant: O=C(O)c1cc[nH]c1
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Br)c(OC2CCN(c3noc(-c4cc[nH]c4)n3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of pyrrole-3-carboxylic acid hydrate (93 mg, 0.723 mmol) in THF (2007 μL) was added oxalyl chloride (264 μL, 3.01 mmol) followed by DMF (10 μL) at 0° C. The mixture was warmed to rt and stirred for 0.5 h. The solvent was evaporated, the residue diluted with THF (1 mL), evaporated again and dried under high vacuum. The residue was diluted with THF (2007 μL), 4-(2-bromo-5-fluorophenoxy)-N′-hydroxypiperidine-1-carboximidamide (200 mg, 0.602 mmol) was added followed by triethylamine (252 μL, 1.806 mmol). The mixture was stirred at rt for 0.5 h, then heated at 80° C. for 1 h. The mixture was cooled to RT and then sodium hydride (72.2 mg, 1.806 mmol) was added. The mixture was stirred at RT for 0.5 h and then heated at 80° C. for 1 h. The solvent was evaporated and the residue diluted with water (2 mL). The aqueous layer was extracted with EtOAc (3×2 mL). The combined organic fractions were dried over Na2SO4 and the solvent was evaporated. Purification by Combiflash chromatography (SiO2-12 g, gradient elution of 30-60% EtOAc/hexanes over 25 min) afforded the title product. 1H NMR (500 MHz, acetone-d6): δ7.61 (s, 2H), 7.11 (s, 1H), 6.99 (s, 1H), 6.75 (s, 1H), 6.65 (s, 1H), 4.89 (s, 1H), 3.76 (s, 2H), 3.54 (s, 2H), 1.99-1.82 (m, 2H), 2.10 (s, 2H). MS: m/z 407, 409 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:15]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)N2CCCCC2)[C:6]=1O)([CH3:4])([CH3:3])[CH3:2].[CH:31]([OH:33])=[O:32]>C1(C)C=CC=CC=1>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]2[O:32][C:31](=[O:33])[CH:15]([C:22]3[CH:23]=[CH:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=3)[C:7]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=CO
Reactant: CC(C)(C)c1cc(C(c2ccc(C#N)cc2)N2CCCCC2)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccc(C#N)cc1
Temperature: 140 °C
Yield: 79.4 %

Procedure:
A solution of 11.33 g (28.0 mmol) of compound (206), prepared according to Example 3a, in 150 ml of dry toluene is degassed using argon and then 33.6 mg (0.057 mmol) of dichloro-[1,3-bis(diphenylphosphino)propane]palladium(II) and 4.22 ml (112 mmol) of formic acid are added. The autoclave is flushed with carbon monoxide and sealed, and a carbon monoxide pressure of 6 bar is then applied. The reaction mixture is maintained at 140° C. for 14 hours. After cooling to room temperature, the reaction mixture is poured into water and extracted three times using ethyl acetate. The organic phases are combined, dried over sodium sulfate and concentrated using a vacuum rotary evaporator. Filtration of the residue on silica gel using ethyl acetate and crystallisation of the pure fractions from methanol yields 7.72 g (79%) of compound (106) (Table 1), m.p. 136-137° C. Molecular weight C23H25NO2 (347.46). Analysis, calculated: C 79.51; H 7.25; N 4.03%. Analysis, found: C 79.36; H 6.98; N 3.82%. 1HNMR (300 MHz, CDCl3, ppm): 1.23 (s, 9H); 1.36 (s, 9H); 4.83 (s, 1H); 6.95 (m, 1H); 7.31 (m, 3H); 7.61 (d, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[N:23]1([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1>C(#N)C.O>[N:23]1([C:29]2[CH:30]=[CH:31][C:32]([NH:33][C:2]3[N:7]=[C:6]([C:8]4[CH:9]=[N:10][N:11]([CH:13]([CH:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)[CH2:14][C:15]#[N:16])[CH:12]=4)[CH:5]=[CH:4][N:3]=3)=[CH:34][CH:35]=2)[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: N#CCC(C1CCOCC1)n1cc(-c2ccnc(Cl)n2)cn1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Solvent: C1COCCO1
Product: N#CCC(C1CCOCC1)n1cc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cn1

Procedure:
A mixture of 3-[4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(tetrahydro-2H-pyran-4-yl)propanenitrile (20 mg, 0.00008 mol), 4-morpholin-4-ylaniline (20.1 mg, 0.000113 mol), and p-toluenesulfonic acid (11 mg, 0.000064 mol) in dry 1,4-dioxane (0.5 mL, 0.006 mol) was refluxed overnight. The mixture was diluted with acetonitrile and water, purified on RP-HPLC at pH 10 to provide the desired product as a racemic mixture (free base). LCMS (M+H) 460.4.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:15]([CH2:33][CH2:34][C:35]1([C:41](=O)[CH3:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C(O)(=O)C.C(=O)([O-])O.[Na+]>ClCCCl.C(Cl)(Cl)Cl>[O:15]([CH2:33][CH2:34][C:35]1([CH2:41][CH2:42][N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[Si:16]([C:29]([CH3:31])([CH3:30])[CH3:32])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C1COCCN1
Reactant: CC(=O)C1(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](OCCC1(CCN2CCOCC2)CCCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 138.6 %

Procedure:
After adding sodium triacetoxyborohydride (0.63 g, 2.98 mmol) to a solution of 1-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]acetaldehyde (1.29 g, ca. 1.97 mmol), morpholine (0.26 mL, 2.98 mmol) and acetic acid (0.23 mL, 4.02 mmol) in 1,2-dichloroethane (5 mL), the mixture was stirred at room temperature for 2.5 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with chloroform. The organic layer was washed with saturated brine and dried (anhydrous sodium sulfate), and then the solvent was distilled off under reduced pressure to obtain the title compound as a brown oil (1.31 g). This was used without purification for the following step.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]([C:26]4[N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:29]=[N:28][N:27]=4)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]2[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]2)=[O:57])[CH3:54])=[O:51])[N:5]=1.C1(C)C=CC=CC=1.CO.C(O)=O>O>[CH3:1][CH2:2][O:3][C:4]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[N:27]=[N:28][NH:29][N:30]=3)=[CH:16][CH:15]=2)[C:11]2[C:10]([C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]3[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64]3)=[O:57])[CH3:54])=[O:51])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1

Procedure:
A solution of trityl candesartan cilexetil (TCC, 30.0 g, 35.17 mmol), toluene (180 mL), methanol (180 mL), formic acid (1.6 g) and water (0.63 g) was refluxed for about 10 h (HPLC control), the solvents were evaporated at 60° C./30 mbar to give a residue as a viscous oil, (about 31 g, theoretical yield of candesartan cilexetil is 21.47 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][N:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CN1C(=O)CCC1.CCOC(C)=O>[N:17]1([C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][N:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: Clc1cccc(-c2n[nH]c3nccnc23)n1
Reactant: C1CNCCN1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: c1cc(-c2n[nH]c3nccnc23)nc(N2CCNCC2)c1
Temperature: 150 °C
Yield: 11 %

Procedure:
A mixture of 3-(6-chloro-2-pyridyl)-1H-pyrazolo[3,4-b]pyrazine (150 mg, 0.6476 mmol) and piperazine (167.4 mg, 1.943 mmol) in NMP (1.5 mL) was heated in microwave at 150° C. for a total of 1.5 h. Mixture cooled to ambient, diluted with EtOAc and washed with sat. NaHCO3 solution (1×), water (2×), brine (1×), dried (MgSO4), filtered and concentrated in vacuo. Crude product purified by ISCO companion (24 g SiO2, 0.5 to 10% MeOH (containing 10% ammonium hydroxide), pure fractions combined and concentrated in vacuo. Product re-dissolved in MeCN/H2O and freeze-dried to leave title compound as a yellow solid (20 mg, 11%). 1H NMR (DMSO-d6) δ2.82 (t, 4H), 3.56 (t, 4H), 6.85 (d, 1H), 7.69 (t, 1H), 7.77 (d, 1H), 8.65 (d, 1H) and 8.73 (d, 1H). ES+281.9.