Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[Li+].[OH-]>C1COCC1.CO.O>[F:36][C:33]([F:34])([F:35])[C:30]1[CH:29]=[CH:28][C:27]([S:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH:8]4[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:37])=[O:2])[CH2:10][CH2:9]4)=[CH:12][CH:13]=3)=[N:18][CH:19]=2)(=[O:26])=[O:25])=[CH:32][CH:31]=1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)cn3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC1CCC(c2ccc(-c3ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 0.136 g (0.256 mmol) of (4-{4-[5-(4-Trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester in THF/MeOH (4:1) was added 0.500 mL of LiOH (4 M) and let stir at r.t. for 72 h. Removed solvent in vacuo. The residue was taken up in water, brought to pH 4 and the solid filtered to afford the title compound. 1H NMR (400 MHz, DMSO d6) δ ppm 1.20-1.31 (m, 2H) 1.55-1.66 (m, 2H) 1.81-1.89 (m, 1H) 1.92-1.97 (m, 4H) 2.27 (d, J=6.82 Hz, 2H) 7.43 (d, J=8.34 Hz, 2H) 7.69 (dd, J=8.59, 2.78 Hz, 1H) 7.97 (d, J=8.59 Hz, 1H) 8.02 (d, J=8.34 Hz, 2H) 8.12 (m, 4H) 8.47 (d, J=0.51 Hz, 1H) 10.96 (br. s., 1H) 12.13 (br. s., 1H); (M+H)+=519.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>CC(C)=O>[OH:12][C:8]1([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:21])[O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:7][CH:6]=2)[CH2:9][O:10][CH2:11]1
Reactant: Nc1ccc(C2(O)COC2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C2(O)COC2)cc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
To a stirred solution of 3-(4-aminophenyl)oxetan-3-ol (1.19 g, 6.66 mmol, 1.0 eq) in acetone (20 mL) was added pyridine (1.05 g, 13.29 mmol, 2.0 eq) and phenyl chloroformate (1.05 g, 6.68 mmol, 1.1 eq) at 0° C. and the mixture was stirred at 0° C. for 30 min. The solvent was evaporated. The resulting residue was purified by CC using EtOAc/PE (3:7) as eluent to get phenyl 4-(3-hydroxyoxetan-3-yl)phenylcarbamate (1.2 g, 63%) as a white solid (TLC system: EtOAc/PE (7:3), Rf: 0.7).
Reaction SMILES: N1C=CC=CC=1.[N:7]1([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][NH:17]3)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.Cl.CN(C)CCCN=C=NCC.[N:34]1([C:40]2[N:41]=[C:42]([CH2:47][C:48]([O-])=[O:49])[NH:43][C:44](=[O:46])[CH:45]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[N:34]1([C:40]2[N:41]=[C:42]([CH2:47][C:48]([N:17]3[C:18]4[C:14](=[C:13]([N:7]5[CH2:8][CH2:9][O:10][CH2:11][CH2:12]5)[CH:21]=[CH:20][CH:19]=4)[CH2:15][CH2:16]3)=[O:49])[NH:43][C:44](=[O:46])[CH:45]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: c1cc2c(c(N3CCOCC3)c1)CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(N3CCOCC3)cccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
8 ml of pyridine, 200 mg of 4-morpholin-4-yl-2,3-dihydro-1H-indole (prepared using 4-bromoindoline as described in WO2007103370) and 330 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are successively added to a solution of 300 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (example 1, step 2) in 8 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 48 hours. After the addition of 50 ml of water and extraction with ethyl acetate, the organic phases are combined and then dried over magnesium sulfate, filtered through sintered glass, and concentrated under reduced pressure. After purification of the residue by silica column chromatography, elution being carried out with a mixture of dichloromethane and 7N ammoniacal methanol (90/10), 180 mg of 6-(morpholin-4-yl)-2-{2-[4-(morpholin-4-yl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}pyrimidin-4(3H)-one are obtained in the form of a purple powder, the characteristics of which are the following:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:14]([C:16]1[O:20][C:19](B(O)O)=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:19]3[O:20][C:16]([CH:14]=[O:15])=[CH:17][CH:18]=3)=[CH:3][CH:4]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: Brc1ccc(C2CCCCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(-c2ccc(C3CCCCC3)cc2)o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 53.3 %

Procedure:
To a round bottom flask containing 1-bromo-4-cyclohexyl-benzene (1.5 g, 6.27 mmol) and 5-formyl-2-furan-boronic acid (1.32 g, 9.41 mmol) in dimethoxyethane (80 mL) and ethanol (20 mL) was added an aqueous solution of sodium carbonate (1:99 g, 18.81 mmol) in water (30 mL) The reaction mixture was stirred at room temperature for 5 minutes, followed by the addition of tetrakis(triphenylphosphine)palladium (358 mg, 0.31 mmol). The reaction mixture was heated at 70° C. for 1 h. The reaction mixture was then cooled to room temperature and diluted with ethyl acetate (500 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated under vacuum. The crude product was purified by silica gel chromatography, eluting with 15% ethyl acetate in hexanes to afford 5-(4-cyclohexyl-phenyl)-furan-2-carbaldehyde (850 mg, 53%) as a solid. 1H NMR (400 MHz, CDCl3): δ 1.28-1.46 (5H, m), 1.75-1.87 (5H, m), 2.53-2.54 (1H, m), 6.79 (1H, d, J=3.6 Hz), 7.26-7.32 (3H, m), 7.73-7.76 (2H, m), 9.63 (1H, s).
Reaction SMILES: [C:1]([O:17][CH3:18])(=[O:16])/[CH:2]=[C:3](\[CH2:5][CH2:6]/[CH:7]=[C:8](/[CH2:10]CC=C(C)C)\[CH3:9])/C.[C:19](Cl)(Cl)(Cl)Cl>>[CH3:19]/[C:2](=[CH:3]\[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])/[C:1]([O:17][CH3:18])=[O:16]
Reactant: ClC(Cl)(Cl)Cl
Reactant: COC(=O)/C=C(/C)CC/C=C(\C)CCC=C(C)C
Product: COC(=O)/C(C)=C/CCC=C(C)C

Procedure:
Gamma-Alkylation of Senecioic Acid (5) with Geranyl Bromide, Farnesoic Acids, (Method B) -- The copper dienolate from 1 g (0.01 mol) of senecioic acid (5) was formed by initial mixed dienolate generation (Method II) and subsequent addition of 3.89 g (0.02 mol) of cuprous iodide, and 5.0 g (0.025 mol) of geranyl bromide was added as in alkylation B. Isolation by procedure 3 and methylation with diazomethane produced 2.06 g (80%) of a mixture of esters. Using glpc analysis (Col. B, 145°), three major product peaks were found in a ratio of 10:36:54, A (retention time of 4 min.): B (retention time of 6.2 min.): C (retention time of 7.3 min.). Peak A was presumed to be the alpha product, and peaks B and C were identified as the isomeric gamma products by pmr (J. W. K. Burrell et al., J. Chem. Soc., 2144(1966)), after isolation by preparative glpc (Col. D). Methyl (Z,E)-farnesoate (Peak B): pmr (CCl4) δ 5.55 (s,1), 5.1-4.9 (m,2), 3.54 (s,3), 2.58 (t,2), 2.2-1.9 (m,6), 1.82 (d, J=0.5 Hz,3), 1.6 (s,3), and 1.4 (s,6).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[CH2:14][O:15][C:16]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>N1C=CC=CC=1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:45]([C:42]2[CH:43]=[CH:44][C:39]([CH3:49])=[CH:40][CH:41]=2)(=[O:47])=[O:46])[CH2:10][C@@H:9]1[CH2:14][O:15][C:16]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(OC[C@H]2C[C@@H](O)CN2C(=O)OC(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(OC[C@H]2C[C@@H](OS(=O)(=O)c3ccc(C)cc3)CN2C(=O)OC(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
(2R,4R)-1-(tert-Butyloxycarbonyl)-2-(4,4'-Dimethoxytrityl) oxymethyl-4-hydroxypyrrolidine 38 (8.09 g, 20.27 mmol) was dissolved in dry pyridine/CH2Cl2 (2:1, 200 ml) and chilled in an ice bath under argon atmosphere. To this cold solution was added TEA (3.03 g, 30 mmol) followed by p-toluenesulphonyl chloride (5.7 g, 30 mmol). The reaction mixture was allowed to stir at 0° C. for 3 h and below 30° C. for 8 h. The reaction mixture was evaporated to dryness, partitioned between EtOAc (200 ml) and 5% NaHCO3 solution (100 ml), and extracted in EtOAc. The EtOAc extract was washed with water (100 ml) and brine (100 ml), dried and evaporated to dryness. The crude product was purified by flash chromatography over silica gel using hexane→EtOAc as the eluent. The pure fractions were pooled together and evaporated to give 12.2 g (89%) of an orange oil. 1HNMR (CDCl3): 1.45 (s, 9H, Boc), 1.90 (dd, 1H), 2.34 (m, 1H), 2.40 (s, 3H, CH3), 3.40-3.62 (m, 3H), 3.74 (s, 6H, 2.OCH3), 4.00 (m, 2H), 4.28 (bs, 1H), 4.44 (m, 1H), 6.82 (d, 4H, Ph), and 7.26-8.00 (m, 13H, Ph).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1I)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:28][C:29]1[C:38]2[NH:37][CH2:36][CH2:35][O:34][C:33]=2[CH:32]=[CH:31][C:30]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1[C:30]1[CH:31]=[CH:32][C:33]2[O:34][CH2:35][CH2:36][NH:37][C:38]=2[C:29]=1[Cl:28])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc3c(c2Cl)NCCO3)OC1(C)C
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(I)n2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(-c3ccc4c(c3Cl)NCCO4)n2n1
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
A mixture of (S)-ethyl 6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (400 mg, 0.817 mmol), 5-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (prepared according to the procedure described in WO 2009/062285; 290 mg, 0.981 mmol) and 2N Na2CO3 (0.817 mL, 1.635 mmol) in DMF (8 mL) was degassed for 15 min. Tetrakis(triphenylphosphine)palladium(0) (66.1 mg, 0.057 mmol) was added and the degassing was continued for another 5 min. The mixture was then heated at 90° C. for 16 h. At this point LCMS indicated completion of reaction and presence of desired product. After cooling to room temperature, water was added (25 mL) and the mixture was extracted with ethyl acetate (2×100 mL), washed with brine (100 mL), dried (Na2SO4), filtered and concentrated. The crude was purified by biotage (5-70% EtOAc/hexane) to afford ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (315 mg, 0.593 mmol, 72.6% yield) as a mixture of two atrope isomers which are not separable (approx 10-15% of minor atrope isomer present by LCMS and NMR). Mixture was used as is in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[CH:16]=2)=[O:13])=[CH:4][CH:3]=1.[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([C:33]3[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=3)=[CH:3][CH:4]=2)=[O:13])=[CH:16][C:17]=1[N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1
Reactant: COc1ccc(NC(=O)c2ccc(Br)c3ccccc23)cc1N1CCN(C)CC1
Reactant: OB(O)c1ccncc1
Product: COc1ccc(NC(=O)c2ccc(-c3ccncc3)c3ccccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from 4-bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]naphth-1-ylcarboxamide (E1) and 4-pyridylboronic acid following a similar procedure to Example 4.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=2)[O:7][N:6]=1)=[O:4].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:39][CH:40]([OH:43])[CH:41]=[CH2:42].C(N(CC)CC)C>CN(C)C=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:42][CH2:41][C:40](=[O:43])[CH3:39])[CH:11]=2)[O:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2cccc(Br)c2)on1
Reactant: C=CC(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2cccc(CCC(C)=O)c2)on1
Temperature: 100 °C
Yield: 59.4 %

Procedure:
To a mixture of 5-(3-Bromo-phenyl)-isoxazole-3-carboxylic acid methyl ester (1.5 g, 5.3 mmol), Pd(OAc)2 (60 mg, 0.27 mmol), P(o-tolyl)3 (162 mg, 0.53 mmol) in anhydrous N,N-dimethylformamide (15 mL) in a pressure tube was added 3-buten-2-ol (0.92 mL, 10.6 mmol) and triethylamine (1.1 mL, 7.95 mmol). The mixture was flushed with nitrogen for 3 minutes, capped and heated to 100° C. for 30 minutes. The reaction mixture was allowed to cool to ambient temperature, partitioned between ethyl acetate and water (75 mL, 1:1). The organic layer was washed with brine (2×25 mL), dried (Na2SO4), filtered, concentrated under reduced pressure and purified on a Silica Gel MPLC eluting with 20–40% ethyl acetate/hexanes to provide the titled compound as a light yellow solid (860 mg, 59%). MS (ESI(+)) m/e 274 (M+H)+.
Reaction SMILES: [H-].[CH2:2]([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]2[C:13]=1[CH2:14][O:15][C:16]2=[O:22].C(OCC)C.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1.CO.[Cl-].[Na+].O>[CH3:2][O:22][CH:16]1[C:17]2[C:13](=[C:12]([CH3:11])[CH:20]=[CH:19][C:18]=2[CH3:21])[CH2:14][O:15]1
Reactant: Cc1ccc(C)c2c1COC2=O
Reactant: CC(C)C[Al+]CC(C)C
Agent: FB(F)F
Agent: [Cl-]
Agent: [H-]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: COC1OCc2c(C)ccc(C)c21
Temperature: -50 °C
Reaction time: 4 h
Yield: 83.6 %

Procedure:
A 1.0M solution of diisobutylaluminium hydride (115 mL, 0.115 mol) in toluene is added dropwise over a period of 30 mins to a stirred solution of 4,7-dimethyl-3H-isobenzofuran-1-one 4 (18.66 g, 0.115 mol) in anhydrous toluene (250 mL) at −15° C. under nitrogen. Anhydrous diethyl ether (100 mL) is added and the reaction mixture is stirred 4 h at −50° C. The reaction mixture is removed from the cooling bath and diethyl ether (300 mL) is immediately added followed by saturated brine (200 mL). The organic layer is separated and the aqueous layer is re-extracted with diethyl ether (200 mL). The combined organics are dried over sodium sulfate and concentrated in vacuo to yield a cream solid. The solid is dissolved in anhydrous methanol (400 mL) and boron trifluoride diethyl etherate (2.3 mL, 0.018 mol) is added at 0° C. and the solution is stirred for 20 h at RT under nitrogen. The reaction mixture is poured into brine (200 mL) and extracted with petrol 40-60 (2×200 mL). The combined extracts are washed with water (3×100 mL), dried over sodium sulphate, and concentrated in vacuo to yield the product 5 as a yellow oil (17.14 g, 84%): 1H-NMR (300 MHz, CDCl3) δ 7.03 (q, 2H, 3J=7.5 Hz, 4.5 Hz), 6.20 (s, 1H), 5.15 (d, 1H, 3J=13.5 Hz), 4.98 (d, 1H, 3J=13 Hz), 3.42 (s, 3H), 2.31 (s, 3H), 2.20 (s, 3H); 13C-NMR (75 MHz, CDCl3) δ 138.7, 135.3, 130.8, 130.2, 129.1, 128.3, 107.7, 72.2, 54.0, 18.1, 17.5.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].S(=O)(=O)(O)O.P(=O)(O)(O)O.[CH:15](=O)[CH:16]([CH3:18])[CH3:17]>>[CH:15]([NH:1][C:2]([NH2:4])=[O:3])([NH:1][C:2]([NH2:4])=[O:3])[CH:16]([CH3:18])[CH3:17]
Reactant: NC(N)=O
Reactant: CC(C)C=O
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Product: CC(C)C(NC(N)=O)NC(N)=O
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
The urea solution was added to the reactor followed by requisite amount of sulfuric acid and phosphoric acid. The mixture was then stirred and heated up to 40° C. The liquid isobutyraldehyde was then added slowly through the dropping funnel and no exotherm was observed and reaction was not initiated. The reaction was run at the same temperature for 30 minutes, but the white solid isobutylidene diurea product was not formed. The GC analysis did not show any significant conversion of isobutyraldehyde. Consequently, the unreacted isobutyraldehyde was ˜100%.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:45]=[CH:44][C:6]([CH2:7][C:8]2[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH:17]=[CH2:18])[CH:11]=[CH:10][C:9]=2[S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH:31]=[CH2:32])=[CH:24][C:23]=2[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)(=[O:21])=[O:20])=[CH:5][CH:4]=1.[CH2:48]([O:50][SiH:51]([O:55][CH2:56][CH3:57])[O:52][CH2:53][CH3:54])[CH3:49]>[Pt].C1(C)C=CC=CC=1>[F:47][C:2]([F:46])([F:1])[C:3]1[CH:45]=[CH:44][C:6]([CH2:7][C:8]2[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][Si:51]([O:55][CH2:56][CH3:57])([O:52][CH2:53][CH3:54])[O:50][CH2:48][CH3:49])[CH:11]=[CH:10][C:9]=2[S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][Si:51]([O:55][CH2:56][CH3:57])([O:52][CH2:53][CH3:54])[O:50][CH2:48][CH3:49])=[CH:24][C:23]=2[CH2:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:38][CH:39]=2)(=[O:20])=[O:21])=[CH:5][CH:4]=1
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCCOc1ccc(S(=O)(=O)c2ccc(OCCC=C)cc2Cc2ccc(C(F)(F)F)cc2)c(Cc2ccc(C(F)(F)F)cc2)c1
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CCO[Si](CCCCOc1ccc(S(=O)(=O)c2ccc(OCCCC[Si](OCC)(OCC)OCC)cc2Cc2ccc(C(F)(F)F)cc2)c(Cc2ccc(C(F)(F)F)cc2)c1)(OCC)OCC
Temperature: 100 °C
Reaction time: 4 h

Procedure:
After 0.61 g of 4-(trifluoromethyl)benzyl-4-(3-butenyloxy)phenyl sulfone and 20 mg of 10% platinum-active carbon were charged in a reaction vessel, and the inside of the vessel was then filled with nitrogen gas, 2 ml of triethoxysilane was added, and the mixture was then further stirred at 100° C. for 4 hours. After the reaction mixture was cooled to room temperature, 20 ml of toluene was added, and the mixture was filtered through a pad of Celite™. After the filtrate was concentrated, dehydrated ethanol was added to the residue, which was then left still over night. After precipitated crystal was removed by filtration, the filtrate was concentrated, and n-hexane was added to collect precipitated crystal by filtration. The obtained crystal was washed with n-hexane to produce 0.53 g of the desired product.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][CH:26]=2)[C:12]2[N:16]([CH2:17][CH2:18][OH:19])[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].O.[NH:35]1[C:39]([NH2:40])=[N:38][N:37]=[N:36]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([N:11]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([NH:40][C:39]3[NH:38][N:37]=[N:36][N:35]=3)=[O:31])=[CH:32][CH:33]=2)[C:12]2[N:16]([CH2:17][CH2:18][OH:19])[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=3[N:13]=2)[CH2:9][CH2:10]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)O)cc2)c2nc3ccccc3n2CCO)CC1
Reactant: Nc1nnn[nH]1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)Nc3nnn[nH]3)cc2)c2nc3ccccc3n2CCO)CC1
Reaction time: 8 h

Procedure:
To a solution of the title compound of Example 10 Step B (0.04 mmol, 19 mg) 1H-tetraazol-5-amine monohydrate (0.13 mmol, 13 mg), HOBt (0.085 mmol, 13 mg) and EDC (0.17 mmol, 33 mg) in 0.5 mL of DMF was added DIEA (0.21 mmol, 36 μL). The reaction mixture was allowed to stand at ambient temperature overnight, then concentrated under reduced pressure. The residue was taken up in ca. 2:1 dioxane/H2O and acidified with TFA, then purified by reverse-phase chromatography (Condition B). The product was lyophilized, affording the title compound as a white solid. MS (ESI): m/z 517 (M+H). HPLC A: 1.81 min.
Reaction SMILES: N1(C2C=CC=CC=2C(N[C@H]2CCC[C@@H]2NC2C=NC(C(F)(F)F)=CN=2)=O)C=CC=N1.Cl.[F:32][C:33]([F:48])([F:47])[C:34]1[N:35]=[CH:36][C:37]([NH:40][C@H:41]2[CH2:45][CH2:44][CH2:43][C@@H:42]2[NH2:46])=[N:38][CH:39]=1.[F:49][C:50]1[CH:51]=[CH:52][C:53]([N:59]2[N:63]=[CH:62][CH:61]=[N:60]2)=[C:54]([CH:58]=1)[C:55](O)=[O:56]>>[F:49][C:50]1[CH:51]=[CH:52][C:53]([N:59]2[N:63]=[CH:62][CH:61]=[N:60]2)=[C:54]([CH:58]=1)[C:55]([NH:46][C@H:42]1[CH2:43][CH2:44][CH2:45][C@@H:41]1[NH:40][C:37]1[CH:36]=[N:35][C:34]([C:33]([F:32])([F:47])[F:48])=[CH:39][N:38]=1)=[O:56]
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Agent: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ccccc1-n1cccn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1cc(F)ccc1-n1nccn1

Procedure:
Prepared according to the procedure for 2-(1H-pyrazol-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 31) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14, 213 mg, 0.75 mmol) and 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 8; 172 mg, 0.83 mmol) except this was then purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3C(OCC3C=CC=CC=3)=O)=[N:9][C:10]=2Br)[CH:5]=[CH:6][N:7]=1.[S:27]1[C:31]2[CH2:32][CH2:33][CH2:34][CH2:35][C:30]=2[N:29]=[C:28]1[NH:36][C:37](=[O:53])[C:38]1[CH:43]=[CH:42][C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][CH:39]=1>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][NH:13]3)=[N:9][C:10]=2[C:41]2[CH:42]=[CH:43][C:38]([C:37]([NH:36][C:28]3[S:27][C:31]4[CH2:32][CH2:33][CH2:34][CH2:35][C:30]=4[N:29]=3)=[O:53])=[CH:39][CH:40]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2ccc(C(=O)Nc3nc4c(s3)CCCC4)cc2)OC1(C)C
Reactant: Nc1nccn2c([C@@H]3CCCN3C(=O)OCc3ccccc3)nc(Br)c12
Product: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4nc5c(s4)CCCC5)cc3)c12
Yield: 60 %

Procedure:
This intermediate was prepared, in an analogous manner as described for intermediate 2, from (S)-benzyl 2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Intermediate 1e) and N-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (intermediate 14b) to afford the title compound (260 mg, 60%).