Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3]P(=O)(OC)OC.O.[OH-].[Li+].[C:18]([O:21][C@@H:22]1[C@H:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[C@@H:25]([CH:37]=O)[C@H:24]([O:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)[CH2:23]1)(=[O:20])[CH3:19]>COC(C)(C)C.O>[C:18]([O:21][C@@H:22]1[C@H:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[C@@H:25](/[CH:37]=[CH:3]/[C:2](=[O:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C@H:24]([O:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)[CH2:23]1)(=[O:20])[CH3:19]
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCCC(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a solution of dimethyl (2-oxoheptyl)phosphonate (12) (0.178 g, 0.801 mmol) in t-butyl methyl ether (2 ml), lithium hydroxide monohydrate (32.5 mg, 0.775 mmol) was added and the mixture was stirred for two hours at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (0.213 g, 0.535 mmol) in t-butyl methyl ether (2 ml) and water (0.12 ml) were added thereto, and the mixed solution was stirred for one hour at room temperature. The reaction mixture was added to water and extracted twice with t-butyl methyl ether. The organic layers were combined, sequentially washed with saturated sodium bicarbonate water and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 100 g; ethyl acetate:hexane=3:7), to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (13) (0.255 g; 0.516 mmol; yield: 96.4%) as a colorless oil.
Reaction SMILES: C(OC(=O)[N:7]([C@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:10]([OH:15])[CH2:11][CH2:12][CH2:13][OH:14])[CH3:8])(C)(C)C.Cl.[C:25](OCC)(=[O:27])[CH3:26]>>[C:25]([O:14][CH2:13][CH2:12][CH2:11][CH:10]([OH:15])[C@H:9]([NH:7][CH3:8])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:27])[CH3:26]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(O)CCCO
Reactant: CCOC(C)=O
Agent: Cl
Product: CN[C@H](Cc1ccccc1)C(O)CCCOC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
((1R)-1-Benzyl-2,5-dihydroxypentyl)methylcarbamic acid tert-butylester (560 mg, 1.52 mmol) was dissolved in ethyl acetate (10 mL). 3M Hydrogen chloride in ethyl acetate (2.0 mL, 6.08 mmol) was added. The solution was stirred at room temp. for 1 h. It was diluted with ethyl acetate (10 mL) and extracted with 1N sodium hydroxide solution (30 mL). The aqueous phase was extracted with ethyl acetate (3×10 mL). The combined organic phases were dried over magnesium sulfate. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (5 mL). The solution was cooled to 0° C. Trifluoroacetic acid (5 mL) was added. The solution was stirred at this temp. for 5 min. The solvents were removed in vacuo. The residue was dissolved in ethyl acetate (10 mL). The solution was extracted with 1N sodium hydroxide solution (10 mL). The aqueous phase was extracted with ethyl acetate (2×5 mL). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g) with dichloromethane/methanol/25% aqueous ammonia 100:10:1 to give 136 mg of (5R)-4-hydroxy-5-(methylamino)-6-phenylhexyl acetate.
Reaction SMILES: C([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH3:20])[C:13](=[O:21])[N:12]([CH2:22][CH2:23][CH3:24])[C:11]=2[N:10]=[C:9]1[CH:25]1[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:26]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH3:33][O:32][C:30]([CH:27]1[CH2:28][CH2:29][CH:25]([C:9]2[NH:8][C:16]3[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH3:20])[C:13](=[O:21])[N:12]([CH2:22][CH2:23][CH3:24])[C:11]=3[N:10]=2)[CH2:26]1)=[O:31]
Reactant: [H][H]
Reactant: CCCn1c(=O)c2c(nc(C3CCC(C(=O)OC)C3)n2Cc2ccccc2)n(CCC)c1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C3CCC(C(=O)OC)C3)nc2n(CCC)c1=O

Procedure:
2.29 g (5.1 mmol) of 7-benzyl-8-(3-methyloxycarbonyl-cyclopentyl)-1,3-dipropylpurine-2,6-dione are hydrogenated in 40 ml of methanol with the addition of 0.5 g of dry Pearlman catalyst until the uptake of hydrogen has ceased at 20° C. under 5.0 bars. After filtering over kieselguhr the solution is evaporated down and the residue is recrystallised from isopropanol. 1.54 g (83.2% of theory) of the title compound are obtained in the form of colourless crystals, melting point 188°-194° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][C:38]=1[O:45][CH3:46])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([O:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:17]3[C:16]4[C:11](=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:13]=[CH:14][CH:15]=4)[N:10]=[CH:9][C:8]=3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:19]=2)=[CH:39][C:38]=1[O:45][CH3:46])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Product: COc1cc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)ccc1OCc1ccccc1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 4-benzyloxy-3-methoxybenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 605.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7]1([CH2:14][CH2:13][CH2:12]1)[C:6]2=[N:15]S(C(C)(C)C)=O.CCOCC>O1CCOCC1>[Br:2][C:3]1[CH:4]=[C:5]2[C:9]([CH2:8][C:7]3([CH2:14][CH2:13][CH2:12]3)[C:6]2=[NH:15])=[CH:10][CH:11]=1
Reactant: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2CC12CCC2
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N=C1c2cc(Br)ccc2CC12CCC2
Reaction time: 3 h

Procedure:
Hydrochloric acid (4M in 1,4-dioxane, 14.89 mL, 59.55 mmol) was added to a solution of N-(5′-bromospiro[cyclobutane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide (Example 54 Step 1, 2.11 g, 5.96 mmol) in anhydrous 1,4-dioxane (60 mL), and the resulting mixture was stirred under an argon atmosphere for 3 h. Et2O (4 mL) was added and the precipitate was filtered off and washed with Et2O, then partitioned between DCM (100 mL), and sat. aq. NaHCO3 (100 mL). The phases were separated and the organic layer concentrated to afford the title compound that was used as such without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][NH:10][C:9]2=[O:19])=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23](=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Cl)[CH3:21]>CN(C=O)C>[CH2:20]([O:22][C:23](=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]1=[O:19])[CH3:21]
Reactant: CCOC(=O)CCCCCCCl
Reactant: O=c1[nH]cc(-c2ccccc2)n1-c1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCn1cc(-c2ccccc2)n(-c2ccc(Cl)cc2)c1=O

Procedure:
The product is obtained as described in example 1 from 1.35 g NaJ (80% suspension in mineral oil), 12.2 g of 1-(4-chlorophenyl)-5-phenyl-4-imidazolin-2-one, 100 cc. of DMF, 8.7 g of 7-chloroenanthic acid ethyl ester and 1.35 g of NaJ. Eluant in chromatographic purification: hexane/ethyl acetate.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>CC(C)=O>[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][C:3]2([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])=[CH:21][CH:20]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: CCOC(=O)C1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(Cc2ccc(C)cc2)CCCC1=O
Yield: 82.4 %

Procedure:
Under vigorously agitation, 39.0 g of ethyl 2-oxocyclopentane carboxylate was added to 105.6 g (purity of 98%) of ground anhydrous potassium carbonate, and after stirring for several minutes, to the mixture was added 100 ml of acetone. The reaction mixture was further stirred for about 15 minutes, then thereto was dropwise added 34.35 ml (purity of 98%) of p-methylbenzyl bromide. Upon the completion of the addition, the reaction mixture was heated for reflux for 4 hours. The reaction mixture was filtered under the reduced pressure, and the filter cake was washed with diethyl ether until its color was purely white. Pale yellow filtrate was collected and dried over anhydrous magnesium sulfate, then the solvent was removed. The residue was distilled under reduced pressure, and 53.57 g of colorless liquid as a distillate cut of 144-146° C./100 Pa was collected. Yield: 82.4%. MS: m/e 260(M+′), 242, 232(M+′—CH2CH2), 215(M+′—OCH2CH3), 187(M+′—CO2CH2CH3), 171, 155(M+″—C8H9) 127, 105(base), 77.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:7]=[CH:8][C:9]=1[O:10]C(=O)C)=[O:3].Cl.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][C@@H:42]([NH2:49])[C:43]3[O:47][N:46]=[C:45]([CH3:48])[N:44]=3)=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)(=[O:28])=[O:27].CCN(C(C)C)C(C)C>>[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][C@@H:42]([NH:49][C:9]([C:4]3[CH:5]=[C:6]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=4)[CH:7]=[CH:8][C:2]=3[OH:3])=[O:10])[C:43]3[O:47][N:46]=[C:45]([CH3:48])[N:44]=3)=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: CC(=O)Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)Cl
Reactant: Cc1noc([C@H](N)Cc2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc([C@@H](Cc2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)NC(=O)c2cc(-c3ccc(C(F)(F)F)cc3)ccc2O)n1

Procedure:
4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2(4′-methanesulfonyl-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (49 mg) was prepared from acetic acid 3-chlorocarbonyl-4′-trifluoromethyl-biphenyl-4-yl ester (1.93 mL, 0.1 M CH2Cl2) and 2-(4′-methanesulfonyl-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine hydrochloride (80 mg, 0.175 mmol) and DIEA (92 μL, 0.525 mmol) using standard procedure M. The crude reaction mixture was concentrated and redissolved in THF (3 mL) and MeOH (1 mL). 1 N NaHCO3 (200 μL) and 1N Na2CO3 (50 μL) were added and the hydrolysis was followed by TLC and LCMS. Once complete, the reaction was diluted with EtOAc and the layers were separated. After extraction and drying the combined organics over MgSO4, the crude mixture was concentrated onto silica gel and purified by chromatography using 15% EtOAc in hexanes.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:33])[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:20]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:20]=[C:19]([CH3:33])[CH:24]=[CH:23][CH:22]=3)=[O:31])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)s2)OCCO1
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(C)c3)n2)s1

Procedure:
Following general procedure X followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-m-tolyl-oxazole-4-carboxylic acid. LC-MS-conditions 05c: tR=0.75 min; [M+H]+=407.22.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]=O)[CH2:7][CH2:6][C:5]2([CH3:15])[CH3:14].[CH2:16]([Mg]Br)[CH3:17].C(OCC)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16]1)[CH2:7][CH2:6][C:5]2([CH3:15])[CH3:14]
Reactant: CC1(C)CCN(C=O)c2ccc(Br)cc21
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)CCN(C2CC2)c2ccc(Br)cc21
Temperature: 50 °C
Yield: 64 %

Procedure:
A stirred, cooled (0° C.) solution of 6-bromo-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-1-carbaldehyde (Intermediate 50, 21.8, 6.7 mmol) in anhydrous tetrahydrofuran (20 mL) under argon was treated with titanium tetra-iso-prop oxide (2.15 mL, 7.39 mmol) followed by 3M solution of ethyl magnesium bromide in diethyl ether (5.6 mL, 16.8 mmol) and the reaction mixture was then heated at 50° C. overnight. It was then cooled in an ice-bath, quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered over celite and evaporated in vacuo to residue which was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title compound as an oil (1.2 g, 64%).
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([N:15]4[CH2:20][CH2:19][CH:18]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:32])OC(C)(C)C)[CH3:24])[CH2:17][CH2:16]4)=[N:12][C:11]=3[CH:33]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[C:35](OCC)(=O)C>>[CH:1]1([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([N:15]4[CH2:16][CH2:17][CH:18]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:32])[CH3:35])[CH3:24])[CH2:19][CH2:20]4)=[N:12][C:11]=3[CH:33]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: C[C@@H](COC1CCN(c2nc3cc(OCC4CCC4)ccc3o2)CC1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COC1CCN(c2nc3cc(OCC4CCC4)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To tert-butyl [(1S)-2-({1-[5-(cyclobutylmethoxy)-1,3-benzoxazol-2-yl]piperidin-4-yl}oxy)-1-methylethyl]carbamate (380 mg) was added 4M hydrogen chloride/ethyl acetate (5 mL), and the mixture was stirred at room temperature for 15 min and concentrated. Pyridine (5 mL) and acetic anhydride (5 mL) were added to the residue, and the mixture was stirred at room temperature for 10 min. After concentration, the residue was purified by silica gel chromatography (NH, hexane/ethyl acetate), and the obtained solid was washed with diethyl ether to give the title compound (158 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][CH2:7][O:8][P:9]([CH2:18][CH:19]([OH:32])[CH2:20][NH:21]C(OCC1C=CC=CC=1)=O)([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])=[O:5])[CH3:2]>C(O)C.[H][H].[Pd]>[CH2:1]([O:3][C:4]([O:6][CH2:7][O:8][P:9]([CH2:18][C@H:19]([OH:32])[CH2:20][NH2:21])([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])=[O:5])[CH3:2]
Reactant: CCOC(=O)OCOP(=O)(CC(O)CNC(=O)OCc1ccccc1)CC1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)OCOP(=O)(CC1CCCCC1)C[C@H](O)CN
Yield: 100 %

Procedure:
(3-Benzyloxycarbonylamino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid ethoxycarbonyloxymethyl ester (0.263 g, 0.56 mmol) was dissolved in absolute ethanol (28 mL) and hydrogenated at RT via a hydrogen Paar shaker for 1 h at 55 psi with 10% Pd/C (0.127 g). The reaction mixture was filtered through celite and concentrated in vacuo to yield the title compound (187 mg, 0.56 mmol) as a foamy white solid. 1H NMR (CDCl3, 300 MHz): 7.90 (bs, 2H), 5.69 (m, 2H), 4.51 (bs, 1H), 4.23 (q, 2H), 3.27 (m, 1H), 3.17 (m, 1H), 2.20 (m, 2H), 1.88-1.64 (m, 8H), 1.34-1.00 (m, 6H), 1.32 (t, 3H). 31P NMR (CDCl3, 300 MHz): 61.14, 59.63. LC/MS m/z: [M+H]+=338.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:20].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C@@H:27]2[CH2:31][CH2:30][C@@H:29]([NH2:32])[CH2:28]2)[CH:22]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:32][C@H:29]2[CH2:30][CH2:31][C@H:27]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH2:28]2)[C:3]=1[F:20]
Reactant: N[C@@H]1CC[C@@H](c2cccnc2)C1
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COc2c(N[C@H]3CC[C@H](c4cccnc4)C3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 91 °C
Reaction time: 7 h
Yield: 16.3 %

Procedure:
A mixture of (3S)-8-amino-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (1.00 g, 3.61 mmol), (1R,3R)-3-(3-pyridyl)cyclopentylamine (702 mg, 4.33 mmol) and diisopropylethylamine (1.38 mL, 7.94 mmol) in anhydrous DMSO (18 mL) was stirred at 91° C. for 7 h. After cooling, the reaction mixture was poured into ice-water and then extracted with CH2Cl2-MeOH. The organic layer was washed with water and brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (EtOAc) to yield (3S)-8-amino-9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-[(1S,3S)-3-(3-pyridyl)cyclopentylamino]-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (247 mg, 16%) as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]([OH:18])[C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=C(OC)N=1.COC1[C:24]2[N:25]([C:31](=[O:42])[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[N:33]=2)C=CC=1C=O>>[OH:18][CH:9]([C:8]1[CH:7]=[CH:6][N:25]2[C:31](=[O:42])[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:40])([CH3:39])[CH3:41])[N:33]=[C:24]2[C:3]=1[O:2][CH3:1])[C:10]#[C:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1c(C=O)ccn2c(=O)n(COCC[Si](C)(C)C)nc12
Reactant: COc1ccc(C(O)C#Cc2ccccc2)c(OC)n1
Product: COc1c(C(O)C#Cc2ccccc2)ccn2c(=O)n(COCC[Si](C)(C)C)nc12
Yield: 100 %

Procedure:
Following the procedure used to prepare 1-(2,6-dimethoxy-pyridin-3-yl)-3-phenyl-prop-2-yn-1-ol, 8-methoxy-3-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde was reacted to give the title compound (1.05 g, 100%) as a pale yellow gum. LCMS (Method A): RT=4.75 min, [M+H]+=426.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:11][CH:12]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13]1)[CH2:7][CH2:8][CH2:9][CH3:10].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCCCCC.O1CCCC1>[C:18]([N:16]1[CH:12]([O:11][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:13][CH2:14][C:15]1=[O:17])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCCCOC1CCC(=O)N1
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCOC1CCC(=O)N1C(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 62.3 %

Procedure:
15.56 cm3 of a 1.5M solution of n-butyllithium in hexane is added at -60° C. to a solution of 4 g of 5-(1-pentyloxy) pyrrolidin-2-one in 80 cm3 of tetrahydrofuran. Agitation is carried out for 15 minutes at -60° C. and then under these conditions a solution of 3.28 g of benzoyl chloride in 20 cm3 of tetrahydrofuran is added. After allowing the temperature to return to ambient, the solvent is evaporated under reduced pressure. The residue is chromatographed on silica (eluent: ethyl acetate-n-hexane 1-3) and 4 g of sought product is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)([CH3:4])([CH3:3])[CH3:2].C1C=NC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:50]([O:54][C:55](=[O:66])[C:56]1[CH:64]=[C:63]([NH2:65])[CH:62]=[C:58]([C:59]([OH:61])=[O:60])[CH:57]=1)([CH3:53])([CH3:52])[CH3:51].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:50]([O:54][C:55](=[O:66])[C:56]1[CH:64]=[C:63]([NH:65][C:21](=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24])[CH:62]=[C:58]([C:59]([OH:61])=[O:60])[CH:57]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)c1cc(N)cc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)Nc1cc(C(=O)O)cc(C(=O)OC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of hexadecandioic acid mono t-butyl ester (100 mg, 0.29 mmol) in dry DCM (2 ml), HOAt (44 mg, 0.29 mmol) and DCC (72 mg, 32 mmol) was added. The mixture was stirred at 50° C. for 1 h. The oil bath was removed. 5-Amino-isophthalic acid mono t-butyl ester (69 mg, 0.29) and DIPEA (0.07 ml, 0.32 mmol) was added. The mixture was stirred at RT over night under nitrogen. The yellow suspension was filtered and the filtrate was concentrated. The residue was redissolved in EtOAc and extracted with 0.1 N HCl (2×), brine (1×), dried (Na2SO4) and concentrated to give a white solid, which was purified twice by flash chromatography using EtOAc/Hept 1:2+5% AcOH. The title compound was obtained in 86% yield (0.140 g) as an oil containing an impurity.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([S:14][CH3:15])[N:11]3[N:16]=[CH:17][CH:18]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(OCC)(=O)C.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>[C:2]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([S:14][CH3:15])[N:11]3[N:16]=[CH:17][CH:18]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CSc1nc(-c2ccc(I)cc2)cc2ccnn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CSc1nc(-c2ccc(-c3ccccc3)cc2)cc2ccnn12
Yield: 77.1 %

Procedure:
Under an inert gas atmosphere is dissolved 5-(4-iodo-phenyl)-7-methylsulfanyl-pyrazolo[1,5-c]pyrimidine (compound D1)(0.45 g) and phenylboronic acid (0.35 g) in dimethoxyethane. To this solution are added bis-(triphenylphosphine)-palladium(II) chloride (0.19 mmol) and an aqueous sodium carbonate solution (2M, 6 ml). The reaction mixture is heated to reflux for 4.5 h. After 1 h further phenylboronic acid (0.2 g) is added in order to complete the reaction. The mixture is diluted with ethyl acetate and filtered over silica gel. The product is partitioned between ethyl acetate and an aqueous solution of sodium bicarbonate (5%), the organic phase is dried over sodium sulfate and the crude product is purified by silica gel flash chromatography. A nearly colorless solid (0.3 g) in 50% yield is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23]CC4C=CC=CC=4)[CH:17]=3)[C:13]([C:31]#[N:32])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[CH:17]=3)[C:13]([C:31]#[N:32])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3cccc(COCc4ccccc4)c3)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3cccc(CO)c3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Cyano-5-[1-(4-ethoxycarbonylphenyl)-1H-purrole-3-yl]benzoic acid was prepared in a similar manner to that described in Example 10 using 4-[3-cyano-4-(3-benzyloxymethylphenyl)pyrrole-1-yl]benzoic acid ethyl ester. To a solution of the obtained carboxylic acid (1.0 g) in tetrahydrofuran (30 mL) was added boran-tetrahydrofuran complex (1.2 mol/L tetrahydrofuran solution, 3.75 mL) at 0° C., and this mixture was stirred at room temperature for 2 hours. To this reaction mixture was added saturated aqueous sodium bicarbonate solution, and this mixture was extracted with diethyl ether. This organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. This residue was purified by column chromatography on silica gel (eluent: methanol/dichloromethane=1/20) to give the title compound (0.21 g).