Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[CH2:5][C:6]([CH3:14])([CH3:13])[O:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24]>CC(C)=O>[CH2:24]([O:12][C:10]1[CH:9]=[C:8]2[C:3]([C:4](=[O:15])[CH2:5][C:6]([CH3:13])([CH3:14])[O:7]2)=[C:2]([OH:1])[CH:11]=1)[CH:23]=[CH2:22]
Reactant: CC1(C)CC(=O)c2c(O)cc(O)cc2O1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(O)c2c(c1)OC(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.5 %

Procedure:
2.81 g of 5,7-dihydroxy-2,2-dimethyl-4-oxochromane was dissolved in 60 ml of acetone. Thereafter, 2.05 g of potassium carbonate and 1.80 g of allyl bromide were added to the reaction solution, and the obtained mixture was then stirred at room temperature for 24 hours. Thereafter, 0.20 g of potassium carbonate and 0.18 g of allyl bromide were further added to the reaction solution, and the obtained mixture was then stirred at room temperature for 10 hours. Thereafter, 0.20 g of potassium carbonate and 0.18 g of allyl bromide were further added to the reaction solution, and the obtained mixture was then stirred at room temperature for 14 hours. Thereafter, 0.20 g of potassium carbonate and 0.18 g of allyl bromide were further added to the reaction solution, and the obtained mixture was then stirred at room temperature for 7 hours. The reaction solution was concentrated under a reduced pressure, and the residue was diluted with ethyl acetate. The resultant product was washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 2.90 g of the subject compound.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[O:4]1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:15]1(=[O:25])[N:19]([CH2:2][CH:3]2[CH2:12][CH2:11][C:10]3[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=3)[O:4]2)[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cccc2c1OC(CO)CC2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc2c1OC(CN1C(=O)c3ccccc3C1=O)CC2
Yield: 80 %

Procedure:
By reacting the compound from Example II with phthalimide in the presence of equimolar amounts of triphenylphosphane and diethyl azodicarboxylate in tetrahydrofuran, the desired product is obtained in 80% yield in the form of a syrup, which is further reacted directly. Rf =0.46 (toluene/ethyl acetate 3:1)
Reaction SMILES: [H-].[Na+].[NH:3]=[C:4]1[NH:8][CH:7]([C:9]2[O:10][C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)[CH2:6][CH2:5]1.N#N.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Cl>CN(C)C=O>[NH:3]=[C:4]1[N:8]([CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[C:30]([O:29][CH3:28])[CH:31]=2)[CH:7]([C:9]2[O:10][C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)[CH2:6][CH2:5]1
Reactant: COc1cccc(CCl)c1
Reactant: N=C1CCC(c2nc(-c3ccccc3)c(-c3ccccc3)o2)N1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(CN2C(=N)CCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.5 %

Procedure:
60% Sodium hydride (289 mg) was added to a stirred solution of 2-(5-imino-2-pyrrolidinyl)-4,5-diphenyloxazole (2.0 g) in N,N-dimethylformamide (20.0 ml) in the presence of an atmospheric N2 gas under ice cooling and the resulting mixture was stirred at the same temperature for 20 minutes and at room temperature for 1 hour 20 minutes. 3-Methoxybenzyl chloride (1.72 g) was added to the mixture under ice cooling and stirring was continued at room temperature overnight. The reaction mixture was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and aqueous sodium bicarbonate, dried over MgSO4, and evaporated in vacuo. The oily residue was chromatographed to afford 2-[5-imino-1-(3-methoxybenzyl)-2-pyrrolidinyl]-4,5-diphenyloxazole (1.80 g) as an amorphous powder.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][N:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:14](=[O:24])[C:13]([C:25](=[O:56])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]4[CH:39]=[CH:38][N:37]=[C:36]([NH:40][CH:41]([C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)[C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:35]=4[Cl:54])=[C:29]([F:55])[CH:28]=3)=[CH:12]2)=[O:8])[CH2:3][CH2:2]1.Cl>C(Cl)Cl>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][N:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:14](=[O:24])[C:13]([C:25](=[O:56])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]4[CH:39]=[CH:38][N:37]=[C:36]([NH:40][CH:41]([C:48]5[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=5)[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:35]=4[Cl:54])=[C:29]([F:55])[CH:28]=3)=[CH:12]2)=[O:8])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)OCn2cc(C(=O)Nc3ccc(Oc4ccnc(NC(c5ccccc5)c5ccccc5)c4Cl)c(F)c3)c(=O)c(-c3ccc(F)cc3)c2)CC1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccnc(NC(c3ccccc3)c3ccccc3)c2Cl)c(F)c1)c1cn(COC(=O)C2CCNCC2)cc(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 107.1 %

Procedure:
To a solution of 4-(3-(4-(2-(benzhydrylamino)-3-chloropyridin-4-yloxy)-3-fluorophenylcarbamoyl)-5-(4-fluorophenyl)-4-oxopyridin-1(4H)-yl)methyl 1-tert-butyl piperidine-1,4-dicarboxylate (135 mg, 0.154 mmol) in DCM (5 mL) at rt, was added HCl (4 N in dioxane, 1 mL). The reaction mixture was stirred at rt for 3 h. The solvents were removed in vacuo and the resulting residue was purified by preparative —HPLC to give the desired product (128 mg) as a white solid. MS (ESI+) m/z 776 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15](=[O:18])[CH2:16][CH3:17])[CH2:9]1)C1C=CC=CC=1>[Pd].CO>[C:19]1([N:14]([CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[C:15](=[O:18])[CH2:16][CH3:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCC(=O)N(c1ccccc1)C1CCCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CCC(=O)N(c1ccccc1)C1CCCNC1
Reaction time: 24 h
Yield: 97.2 %

Procedure:
A mixture of N-(1-benzyl-piperidin-3-yl)-N-phenyl-propionamide (165) (150 mg) and Pd—C(10%, 50 mg) and MeOH (50 ml) was stirred under H2 (1 atm) for 24 hr. The catalyst was removed by filtration through Celite to give 166 as a colorless oil (105 mg, 97%). 1H-NMR (300 MHz, CDCl3) δ 7.41 (m, 3H), 7.10 (m, 2H), 3.20 (m 1H), 2.90 (m, 1H), 2.40–2.20 (m, 2H), 1.90 (m, 2H), 1.60 (m, 4H), 1.20 (m, 1H), 1.00 (t, 3H) ppm; LRMS (calculated for C14H21N2O) (M+1)+ 233. found 233.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C([O-])(=O)C1C(=CC=CC=1)O.[Na+].[Na].[Cl-].[Zn+2:24].[Cl-]>>[Zn:24].[C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: [Zn+2]
Agent: O=C(O)c1ccccc1O
Agent: O=C([O-])c1ccccc1O
Agent: [Cl-]
Product: [Zn]

Procedure:
The aforementioned metallic salt of salicylic acid derivative can be easily synthesized by the method described in CLARK, J, L, Kao, H(1948) J. Amer. Chem. Soc. 70,2151. For instance, 2 moles of sodium salicylate (or a sodium salt of a salicylic acid derivative) and 1 mole of zinc chloride are added to a solvent and mixed. The thus obtained mixture is heated with stirring, thereby obtaining a zinc salt of a salicylic acid.
Reaction SMILES: [H-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[OH:13])[CH:6]=[CH:5][CH:4]=1.Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C.O>[CH3:21][C:15]([O:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[N:3]=[CH:4][CH:5]=[CH:6]2)([CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: Oc1cccc2cccnc12
Reactant: CCOC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1cccc2cccnc12
Reaction time: 0.08 h
Yield: 44.8 %

Procedure:
To a solution of compound NaH (248 mg, 10.2 mmol) in DMF (10 mL) was added quinolin-8-ol (500 mg, 3.44 mmol) at 28° C. After stirring for 5 minutes, ethyl 2-bromo-2-methylpropanoate (806 mg, 4.13 mmol) was added and the reaction mixture was stirred for an additional 16 h at 28° C. until the reaction was complete by TLC. The mixture was then diluted with water (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the crude product (400 mg, 44.8%) as colorless oil which was used in next step without further purification.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[OH:7].[C:8]1([C:14](Cl)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[C:8]1([C:14]([NH:1][C@@H:2]2[CH2:6][CH2:5][CH2:4][C@H:3]2[OH:7])([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N[C@@H]1CCC[C@H]1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O[C@@H]1CCC[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of trans-2-aminocyclopentanol (45.84 mmol), triphenylmethylchloride (11.50 g; 41.26 mmol) and triethylamine (15.97 ml; 114.60 mmol) in 100 ml CH2Cl2 is refluxed overnight. The reaction mixture is cooled and concentrated in vacuo and flash chromatographed using 5:1; hexane:EtOAc to obtain trans-2-triphenylmethylaminocyclopentanol which is used directly in the next step.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[N:3]=1.Cl.Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][CH:30]=1)[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>CCO>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([C:2]3[S:6][N:5]=[C:4]([C:7]4[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=4)[N:3]=3)[CH2:26][CH2:27]2)[CH:28]=[CH:29][CH:30]=1
Reactant: Clc1nc(-c2ccncc2)ns1
Reactant: COc1cccc(CCN2CCNCC2)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CCN2CCN(c3nc(-c4ccncc4)ns3)CC2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 15.5 %

Procedure:
A mixture of 5-chloro-3-(pyridin-4-yl)-1,2,4-thiadiazole (42 mg, 213 μmol), 1-(3-methoxyphenethyl)piperazine dihydrochloride (62.3 mg, 213 μmol) and DIPEA (137 mg, 186 μl, 1.06 mmol) in 10 mL EtOH was stirred for 2.5 h at RT the mixture was filtered, washed with EtOH and dried in vacuo at 50° C. for 2 hours to yield 12.6 mg (15%) of the title compounds as orange solid. MS (m/e): 382.2 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([N+:20]([O-:22])=[O:21])[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1.N1C(=O)CC[C@H]1C(O)=O.Cl>>[OH:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[O:10][C:6]3[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][C:3]([OH:2])=[CH:19][C:7]=3[CH:8]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(-c2cc3cc(OC)cc([N+](=O)[O-])c3o2)cc1
Agent: Cl
Agent: O=C1CC[C@@H](C(=O)O)N1
Product: O=[N+]([O-])c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Temperature: 200 °C
Yield: 47.3 %

Procedure:
A mixture of 98 (0.56 g) and Pyr-HCl and heated at 200° C. for 1 h (while occasionally adding more Pyr-HCl). The reaction was allowed to cool and then partitioned between 2 N HCl aq and EtOAc. A small amount of MeOH was added to facilitate the dissolution process. The organic layer was washed with saturated NaHCO3 aq, brine, and dried over MgSO4. Filtration, concentration and trituration of the pdt with CH2Cl2 yielded 0.44 g of the desired pdt which contained some inorganic impurities. The material was then chromatographed on silica gel (MeOH/CH2Cl2 1:19 to MeOH/CH2Cl2 1:9) to yield 0.24 g of 99: Mp=236-237° C.; 1H NMR (DMSO-d6) δ 10.06 (br s, 1 H), 7.73 (d, 2 H, J=8.3 Hz), 7.46 (dd, 1 H, J=2.4 Hz, 0.7 HZ), 7.38 (dd, 1 H, J=2.3 Hz, 0.7 Hz), 7.28 (s, 1 H), 6.93 (d, 2 H, J=8.3 Hz); MS 270 (M−H)−.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH2:9]1.Cl[C:17]1[N:22]=[C:21]([NH:23][C@H:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH3:25])[N:20]=[C:19]([NH:33][C:34]2[CH:39]=[N:38][CH:37]=[CH:36][N:35]=2)[CH:18]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O1CCOCC1.C(N(CC)CC)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C@@H:24]([NH:23][C:21]2[N:22]=[C:17]([N:8]3[CH2:11][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH2:9]3)[CH:18]=[C:19]([NH:33][C:34]3[CH:39]=[N:38][CH:37]=[CH:36][N:35]=3)[N:20]=2)[CH3:25])=[CH:27][CH:28]=1
Reactant: CC(=O)NC1CNC1
Reactant: C[C@H](Nc1nc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)NC1CN(c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)C1
Temperature: 90 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
100 mg of t-butyl azetidin-3-ylcarbamate was dissolved in 5 ml of methylene chloride, and 225 mg of N,N-diisopropylethylamine was added. Under ice-cooling, the reaction mixture was added with 68 mg of acetyl chloride, and stirred at room temperature for 2 days. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with 5% citric acid aqueous solution and brine in turn, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 146 mg of a brown oily matter. The obtained residue was dissolved in 2.5 ml of methylene chloride, and 1 ml of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and then 66 mg of N-(azetidin-3-yl)acetamide trifluoroacetate was obtained. Subsequently, 33 mg of N-(azetidin-3-yl)acetamide trifluoroacetate, 148 mg of triethylamine, 100 mg of (S)-6-chloro-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine, 28 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 56 mg of sodium t-butoxide and 30 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 3 ml of degassed 1,4-dioxane, and the mixture was stirred at 90° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 17 mg of the objective compound as bright golden yellow powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH:6]1[CH2:12][CH:11]2[N:13]([C:14]3[C:15]4[C:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[C:21]([C:29]([NH:31][CH:32]([CH3:34])[CH3:33])=[O:30])[S:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:8]([CH2:9][CH2:10]2)[CH2:7]1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[CH:32]([NH:31][C:29]([C:21]1[S:20][C:16]2[N:17]=[CH:18][N:19]=[C:14]([N:13]3[CH:11]4[CH2:10][CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][S:43]([CH3:42])(=[O:45])=[O:44])[CH2:12]4)[C:15]=2[C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:30])([CH3:34])[CH3:33]
Reactant: CC(C)NC(=O)c1sc2ncnc(N3C4CCC3CC(COCCN)C4)c2c1-c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NC(=O)c1sc2ncnc(N3C4CCC3CC(COCCNS(C)(=O)=O)C4)c2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.8 %

Procedure:
4-[3-(2-aminoethoxymethyl)-8-azabicyclo[3.2.1]octan-8-yl]-N-isopropyl-5-phenyl-thieno[2,3-d]pyrimidine-6-carboxamide (0.1 g, 0.2 mmol) and was stirred in DCM (10 mL) at 0° C. Triethylamine (0.04 g, 0.06 mL, 0.4 mmol) was added followed by methanesulfonyl chloride (0.04 g, 0.02 mL, 0.3 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The solvent was removed at reduced pressure. The resulting residue was taken up in DCM, washed with water, dried over Na2SO4 and concentrated at reduced pressure. The resulting residue was purified by acidic prep HPLC (method 1). Desired fractions were combined and concentrated at reduced pressure. The residue was taken up in DCM, washed with sat. NaHCO3 solution, the organic dried over Na2SO4 and concentrated at reduced pressure to afford N-isopropyl-4-[3-[2-(methanesulfonamido)ethoxymethyl]-8-azabicyclo[3.2.1]octan-8-yl]-5-phenyl-thieno[2,3-d]pyrimidine-6-carboxamide (41 mg).
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][N:33]4[CH2:36][CH:35]([OH:37])[CH2:34]4)[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][N:33]4[CH2:36][CH:35]([OH:37])[CH2:34]4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCN4CC(O)C4)c4ccc(OC(F)F)cc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CCCN4CC(O)C4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.2 %

Procedure:
To a pale yellow solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(3-hydroxyazetidin-1-yl)propyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (43 mg, 66.8 μmol) in dichloromethane (4.00 mL) was added TFA (740 mg, 0.5 mL, 6.49 mmol, Eq: 97.2), the reaction mixture turned orange and was stirred at 25° C. for 18 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 a yellow foam, which was dissolved in dichloromethane (with few drops of MeOH) and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 10% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane and cyclohexane added to allow solid formation, off-white solid was separated by decantation and dried under high vacuum to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(3-hydroxyazetidin-1-yl)propyl)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (21 mg, 40.9 μmol, 61.2%). MS (M+H)+=514; 1H NMR (DMSO-d6) δ: 9.06 (s, 1H), 8.37 (s, 1H), 8.19 (s, 1H), 7.81-7.91 (m, 2H), 7.39 (d, J=8.7 Hz, 1H), 7.19 (t, J=74.4 Hz, 1H), 5.23 (d, J=6.4 Hz, 1H), 4.53 (t, J=6.6 Hz, 2H), 4.07-4.25 (m, 1H), 3.50 (t, J=6.4 Hz, 2H), 2.62 (t, J=6.8 Hz, 2H), 2.35 (t, J=6.8 Hz, 2H), 1.78-2.01 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.[CH3:17][O:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:17][O:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:8](=[O:10])[CH2:7][C:4]2[CH:3]=[CH:2][C:1]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:6][CH:5]=2)[CH:21]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(NC(=O)Cc2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a solution of the 4-biphenyl acetic acid (106.1 mg, 0.50 mmol), 3-amino benzoic acid methyl ester (113.4 mg, 0.75 mmol), EDCHCl (143.8 mg, 0.75 mmol) and HOBT (101.4 mg, 0.75 mmol) were dissolved in DMF (5.0 mL), and DIPEA (0.13 mL, 0.75 mmol) were added. The reaction mixture was stirred at room temperature overnight and then partitioned between Ethyl acetate and brine. The organic phase was dried (anhydrous MgSO4), and concentrated. Purification by silica gel column chromatography (n-Hexane: Ethyl acetate:MeOH=6:3:1) gave 3-(2-biphenyl-4-yl-acetyl-amino)benzoic acid methyl ester as a white solid (174 mg, 100% yield).
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:3][CH:4]=[CH:5][C:6](=[O:8])[CH3:7]>[Cr]([O-])([O-])=O.[Cu+2]>[CH3:12][CH:10]([CH2:9][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([OH:8])[CH3:7])[CH3:11]
Reactant: CC(=O)C=CC=C(C)CC(C)C
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Product: CC(C)CC(C)CCCC(C)O
Temperature: 100 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
200 g of freshly distilled 6,8-dimethyl-3,5-nonadien-2-one and 2 g of copper chromite are placed in a 1 liter steel autoclave which is provided with a magnetic stirrer (Autoclave Engineers, Inc.). The autoclave is flushed with hydrogen and it is firstly placed under a pressure of 30 bar of hydrogen. The autoclave is now heated rapidly to 100° C. and then slowly within 3 hours to 170° C. The pressure is then adjusted to 50 bar and the temperature is fixed at 200° C. The theoretical amount of hydrogen to be absorbed amounts to 90 liters. The autoclave is held at a pressure of 50 atmospheres and in a temperature range between 180°-200° C. After 5 hours, 7% of unsaturated material is still present in the mixture. The hydrogenation is continued for a further 6 hours in order to reduce the amount of non-hydrogenated product to 0.2%. The resulting crude product is separated from the catalyst by filtration and then distilled. There are obtained 171 g (83%) of chemically pure 2,4-dimethyl-nonan- 8-ol of boiling point 91° C./6 mmHg; nD20 =1.4368. 136 g of this product are designated at being olfactorily good (yield 83% or 65.7% respectively).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O>>[Cl:12][CH2:13][C:14]1[N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:8][CH:16]=1
Reactant: COc1ccc(C(N)=O)cc1
Reactant: O=C(CCl)CCl
Product: COc1ccc(-c2nc(CCl)co2)cc1
Yield: 78 %

Procedure:
This compound was synthesized from 4-methoxybenzamide and 1,3-dichloroacetone as described in example 74 step 1 (2.3 g, yield 78%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.98-7.96 (d, J=8.3 Hz, 2H), 7.65 (s, 1H), 6.97-6.95 (d, J=8.3 Hz, 2H), 4.56 (s, 2H), 3.86 (s, 3H). MS (ESI) m/z: Calculated for C11H10ClNO2: 223.04. found: 223.8 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][C:9]=1[F:15])(=[O:3])[CH3:2].[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:31]2[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=2)=[CH:10][C:9]=1[F:15])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)cc1F
Reactant: OB(O)c1ccncc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2ccncc2)cc1F
Yield: 51 %

Procedure:
By carrying out the operation analogously to example 3, starting from 4-bromo-2-fluorophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VI, and 4-pyridineboronic acid, the expected product is obtained in the form of a white solid with a yield of 51%.