Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([O:31][CH2:32][CH3:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[ClH:35]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:34])[CH:4]([O:31][CH2:32][CH3:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:13][CH2:14]2)=[CH:8][CH:7]=1.[ClH:35]
Reactant: CCCCCCCN(CC1(c2ccc(CC(OCC)C(=O)OC)cc2)CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCCCCNCC1(c2ccc(CC(OCC)C(=O)OC)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 3-(4-{1-((tert-butoxycarbonyl-heptyl-amino)-methyl]-cyclopropyl}-phenyl)-2-ethoxy-propionic acid methyl ester (1.29 mmol, 615 mg) in ethyl acetate (20 mL) under a nitrogen atmosphere was cooled to −78° C., and saturated with HCl gas. The solution was allowed to warm to room temperature and the solvent was evaporated, leaving the 2-ethoxy-3-[4-(1-heptylaminomethyl-cyclopropyl)-phenyl]-propionic acid methyl ester as its HCl salt (531 mg, 100%).
Reaction SMILES: ClC(Cl)(Cl)C([NH:5][CH:6]([CH:14]=[CH2:15])[CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=O>Cl>[NH2:5][CH:6]([CH:14]=[CH2:15])[CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: C=CC(CCC(=O)OCC)NC(=O)C(Cl)(Cl)Cl
Agent: Cl
Product: C=CC(N)CCC(=O)O
Yield: 139.4 %

Procedure:
A suspension of ethyl 4-trichloroacetoamido-5-hexenoate (0.3 g, 1 mmol) in 6N HCl (10 mL) was heated under reflux 6H. Then the mixture was concentrated in, vacuo, diluted with water (10 mL), washed twice with Acoet, and dried in vacuo to give the title product (0.18 g, 100%). NMR, TLC (NH4OH:EtOH, 3:7) are identical with those of an authentic sample of 4-amino-5hexenoic acid. 1H NMR (90 MHz) (D2), δ ppm. (TMS) 1.83 (m, 2H, CH2CO2), 2.33 (m, 2H, CH2CH2) 3.66 (m, 1H, CH--C=), 5.35 (m, 3H, CH2 =CH) .
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:28]([C:30]1[C:38]2[C:33](=[CH:34][C:35]([Cl:40])=[CH:36][C:37]=2[Cl:39])[NH:32][C:31]=1[C:41]([O:43][CH2:44][CH3:45])=[O:42])=O>>[C:1]([O:5][C:6]([CH:8]=[CH:28][C:30]1[C:38]2[C:33](=[CH:34][C:35]([Cl:40])=[CH:36][C:37]=2[Cl:39])[NH:32][C:31]=1[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1C=O
Reactant: CC(C)(C)OC(=O)C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1C=CC(=O)OC(C)(C)C
Yield: 67.8 %

Procedure:
A solution of tertbutoxycarbonylmethyltriphenylphosphorane (5.33 g) and ethyl 3-formyl-4,6-dichloroindole-2-carboxylate (3 g) in dioxanlacetonitrile (1;1; 60 ml) was stirred at 60° for 7 hours. The solvent was evaported under reduced pressure and the residual oil was purified by chromatography, eluting with cyclohexane and ethyl acetate 7/3, to obtain the title compound (2,73 g) tlc EA/CH: 3/7; Rf=0.35.
Reaction SMILES: Cl.[CH2:2]([NH:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C@@H:23]([C:25]([O:27][CH3:28])=[O:26])[NH2:24])[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)=[O:7])[CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.[NH4+].[Cl-].[C:40]([O:43][CH2:44][CH3:45])(=[O:42])C>C1COCC1>[CH2:44]([O:43][C:40]([NH:24][C@H:23]([C:25]([O:27][CH3:28])=[O:26])[CH2:22][O:21][C:17]1[CH:16]=[C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6]([NH:5][CH2:2][CH2:3][CH3:4])=[O:7])[CH:10]=2)[CH:20]=[CH:19][CH:18]=1)=[O:42])[CH3:45]
Reactant: CCCNC(=O)Nc1cccc(-c2cccc(OC[C@H](N)C(=O)OC)c2)c1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)Nc1cccc(-c2cccc(OC[C@H](NC(=O)OCC)C(=O)OC)c2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound of Example 6 (256.0 mg, 0.63 mmol, 1 equiv) was suspended in THF (3 mL) and cooled to 0° C. Ethyl chloroformiate (88.5 mg, 0.82 mmol, 1.3 equiv) was added dropwise followed by N,N diisopropylethylamine (234.3 mg, 1.88 mmol, 3 equiv). The reaction mixture was allowed to warm to room temperature and stirred for one hour. It was worked up by addition of sat. aqueous NH4Cl soln. and ethyl acetate. The phases were separated and the organic layer was dried over NaSO4. After filtration and evaporation of the solvents the crude product was purified by chromatography (SiO2 CH/EtOAc 90:10). Yield 210.0 mg, 75.4% of a white solid. 1H NMR (CDCl3, 300 MHz) δ 7.50 (s, 1H); 7.39-7.25 (m, 3H); 7.21 (d, 1H), 7.12 (d, 1H); 7.05 (s, 1H); 6.90 (brs, 1H); 6.81 (d, 1H); 5.80 (d, 1H); 5.10 (m, 1H); 4.75-4.65 (m, 1H); 4.42 (dd, 1H); 4.25 (dd, 1H); 4.20-4.10 (m, 2H); 3.79 (s, 3H); 3.20 (dd, 2H); 1.52 (sext, 2H); 1.22 (t, 3H); 0.95 (t, 3H). MS (DCI/NH3) 461 (M+NH4), 444 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>C1COCC1>[S:11]([N:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: c1cc[nH]c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cccc2)cc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a stirred solution of 1H-pyrrole (5.0 g, 74.6 mmol) in dry THF (50 mL) was added n-BuLi (32.8 mL, 2.5 M) at −78° C. and stirred at this temperature for 30 min. Then a solution of TsCl (14.2 g, 74.6 mmol) in dry THF (100 mL) was added at −78° C. The mixture was stirred at rt overnight, quenched with water and extracted with EA twice. The combined organic layers were washed with brine and concentrated to give crude compound 27a (14.2 g, 86%) as a solid.
Reaction SMILES: [C:1]([O:10][CH2:11][C:12]([O:14][CH2:15][C:16]([OH:18])=O)=[O:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(Cl)(=O)C([Cl:22])=O>>[C:1]([O:10][CH2:11][C:12]([O:14][CH2:15][C:16]([Cl:22])=[O:18])=[O:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCC(=O)OCC(=O)OCC(=O)O
Product: CCCCCCCC(=O)OCC(=O)OCC(=O)Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5.6 g (0.22 mole) octanoyl-oxyacetyl-oxyacetic acid, 50 ml hexame were placed in a 250 ml round bottom flask. 2.9 ml (0.03 mole) oxalyl chloride was added in one portion and the reaction stirred at room temperature for 6 hours. The reaction was then heated to 80° C., a distillation head attached with condenser and receiver, and the excess oxalyl chloride and solvent removed at reduced pressure. There remained 4.5 g of light yellow oil. IR spectrum reveals no free --OH and a broad v--C=O absorbance, with maxima at 1815, 1780 and 1755 cm-1.
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]([O:24][CH3:25])[C:5]2[N:6]([CH2:18][CH2:19][O:20][CH3:21])[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[Li]CCCC.[F:31]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>C1COCC1>[F:31][C:2]1[CH:23]=[C:22]([O:24][CH3:25])[C:5]2[N:6]([CH2:18][CH2:19][O:20][CH3:21])[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Br)cc(OC)c21
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(F)cc(OC)c21
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 11.9 %

Procedure:
To a solution of 400 mg (0.98 mmol) 5-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole in 3 ml dry THF, n-BuLi (0.740 ml, 1.18 mmol) is added slowly at −78° C. After stirring for 45 min. at −78° C. N-fluoro-bis(phenylsulfonyl)amine (568.7 mg, 1.77 mmol) is added. Stirring at −78° C. is continued for another hour and then the reaction mixture is warmed to room temperature. After that the reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (3×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=2:1−>1:1) to afford 40 mg of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[N:16]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[N:15]=[C:14]([Cl:24])[CH:13]=3)[O:8][C:7](=[O:25])[C:6]=2[CH:5]=[C:4](I)[CH:3]=1.[Cu][C:28]#[N:29]>O1CCCC1.C(OCC)(=O)C.[Cu]I>[Cl:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[N:16]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[N:15]=[C:14]([Cl:24])[CH:13]=3)[O:8][C:7](=[O:25])[C:6]=2[CH:5]=[C:4]([C:28]#[N:29])[CH:3]=1
Reactant: O=c1oc(-c2cc(Cl)nn2-c2ncccc2Cl)nc2c(Cl)cc(I)cc12
Reactant: N#C[Cu]
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cc(Cl)c2nc(-c3cc(Cl)nn3-c3ncccc3Cl)oc(=O)c2c1

Procedure:
To a solution of 8-chloro-2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-iodo-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Step B) (575 mg, 1.1 mmol) in tetrahydrofuran (15 mL) was added copper(I) iodide (840 mg, 0.44 mmol), tetrakis(triphenyphosphine)palladium(0) (255 mg, 0.22 mmol) and copper(I) cyanide (500 mg, 5.5 mmol) sequentially at room temperature. The reaction mixture was then heated at reflux overnight. The reaction turned black in color, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The reaction was diluted with ethyl acetate (20 mL) and filtered through Celite®, followed by washing three times with 10% aqueous sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure to afford 375 mg of the title compound as a crude yellow solid.
Reaction SMILES: C([O:3][P:4]([CH2:9][C@@H:10]1[C@H:15]([NH:16][C:17](=[O:19])[CH3:18])[C@@H:14]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:13]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:12]([CH2:36][O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:11]1)(=[O:8])[O:5]CC)C.N1C=CC=CC=1.C[Si](Br)(C)C>C(#N)C>[C:17]([NH:16][C@@H:15]1[C@@H:14]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:13]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:12]([CH2:36][O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:11][C@@H:10]1[CH2:9][P:4](=[O:3])([OH:5])[OH:8])(=[O:19])[CH3:18]
Reactant: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1NC(C)=O)OCC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(=O)N[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H]1CP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 123.4 %

Procedure:
To a solution of diethyl(((2S,3R,4R,5S,6R)-3-acetamido-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)phosphonate (0.40 g, 0.64 mmol, 1.0 equiv) in dry acetonitrile (23.5 mL) was added pyridine (0.6 mL, 7.36 mmol, 11.5 equiv) at 0° C. under argon atmosphere. Then, anhydrous TMSBr (1.65 mL, 10.2 mmol, 16.0 equiv) dissolved in 16.5 mL of dry acetonitrile was added dropwise at −5 to 0° C. The resulting mixture was stirred for 10 minutes. The resulting reaction mixture was allowed to warm to room temperature 4 hours and then the volatiles were removed in vacuo (bath temperature <15° C.). To the residue was added ice-cold water (10 mL), and the organic material was extracted into DCM (2×10 mL). The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo (bath temperature <15° C.) to obtain (((2S,3R,4R,5S,6R)-3-acetamido-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)phosphonic acid (0.45 g) as a pale green solid. This material was directly taken forward to the next step without purification. ESI (M+1) 570.0; calc for C30H36NO8P 569.2.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=3[F:25])[CH:9]=2)=[CH:6][N:5]=[CH:4]1)[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34](=[O:39])[CH2:35][C:36](O)=[O:37].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([N:3]1[C:7]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:24]=[CH:23][C:21]([NH:22][C:36](=[O:37])[CH2:35][C:34]([NH:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[F:26])=[O:39])=[CH:20][C:19]=3[F:25])[CH:9]=2)=[CH:6][N:5]=[CH:4]1)[CH3:2]
Reactant: O=C(O)CC(=O)Nc1ccccc1F
Reactant: CCn1cncc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCn1cncc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccccc4F)cc3F)c2s1
Reaction time: 1 h
Yield: 60.4 %

Procedure:
To a solution of the amino compound 120 (400 mg, 1.08 mmol) in DMF (10 mL), 3-(2-fluorophenylamino)-3-oxopropanoic acid (444 mg, 2.25 mmol), EDC (519 mg, 2.70 mmol) was added HOBT (364 mg, 2.70 mmol). The reaction mixture was allowed to stir for 1 hr. The solution was extracted with EtOAc and the extract was washed with water, aqueous ammonium chloride and brine then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (eluents DCM-MeOH, 98:2, 95:5) to afford title compound 117 (348 mg, 58% yield) as a white solid. 1H NMR (DMSO-d6). δ ppm: 10.58 (s, 1H), 10.06 (s, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.10-7.76 (m, 1H), 7.94 (d, J=1.2 Hz, 1H), 7.88 (dd, J=2.4 and 13.2 Hz, 1H), 7.74 (s, 1H)), 7.51 (t, J=8.8 Hz, 1H), 7.43 (dd, J=1.6 and 8.8 Hz, 1H), 7.39 (d, J=1.2 Hz, 1H), 7.32-7.25 (m, 1H), 7.21-7.14 (m, 2H), 6.66 (d, J=5.6 Hz, 1H), 4.29 (q, J=7.2 Hz, 2H), 3.62 (s, 2H), 1.34 (t, J=7.2 Hz, 3H). MS (m/z): 534.1 (M+H).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.[O:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[N:21]=[C:22]([NH:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)C4CNCC[C:24]=4[N:25]=3)=[CH:15][CH:14]=2)=[CH:11][N:10]=[CH:9]1.IC>CN(C=O)C.O1CCOCC1>[CH3:1][N:3]1[CH2:6][CH2:7][C:24]2[N:25]=[C:20]([NH:19][C:16]3[CH:17]=[CH:18][C:13]([C:12]4[O:8][CH:9]=[N:10][CH:11]=4)=[CH:14][CH:15]=3)[N:21]=[C:22]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:5]=2[CH2:4]1
Reactant: CCN(CC)CC
Reactant: c1ccc(Nc2nc(Nc3ccc(-c4cnco4)cc3)nc3c2CNCC3)cc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CI
Product: CN1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(Nc3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
Triethylamine (0.022 mL, 0.16 mmol) was added to N2-(4-(oxazol-5-yl)phenyl)-N4-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (0.06 g, 0.16 mmol, Example 3) in DMF (1 mL) and dioxane (1 mL). Iodomethane (0.031 g, 0.22 mmol) was added and the reaction stirred at 25° C. for 1 h. Solvent was removed under reduced pressure and the crude product redissolved in DMSO. The crude product was purified by preparative HPLC to give 6-methyl-N2-(4-(oxazol-5-yl)phenyl)-N4-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (0.014 g, 23%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:27])[CH2:19][O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[CH:44][C:45]([NH2:48])=[N:46][CH:47]=2)O1>>[NH2:48][C:45]1[N:46]=[CH:47][C:42]([C:2]2[N:3]=[C:4]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:27])[CH2:19][O:20][CH:21]5[CH2:26][CH2:25][CH2:24][CH2:23][O:22]5)[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:43][CH:44]=1
Reactant: O=C(COC1CCCCO1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(=O)COC5CCCCO5)CC4)cc3n2)cn1

Procedure:
1-(4-((2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-(tetrahydro-2H-pyran-2-yloxy)ethanone prepared via General Procedure B-3 (250 mg) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via General Procedure A to give 1-(4-((2-(6-aminopyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-(tetrahydro-2H-pyran-2-yloxy)ethanone.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.S([O-])([O-])(=O)=O.[Na+].[Na+].[NH2:17][CH:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21].[BH4-].[Na+]>ClCCl.CO>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:17][CH:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1ccccc1Br
Reactant: CCCC(N)CCC
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCC(CCC)NCc1ccccc1Br
Reaction time: 2 h
Yield: 95 %

Procedure:
Added to a solution of 7.4 g of 2-bromobenzaldehyde in 80 cm3 of dichloromethane are 6.25 g of sodium sulfate and 5.07 g of 4-aminoheptane at a temperature close to 20° C. After stirring for 2 h, the reaction mixture is filtered through a cartridge and washed with 2 lots of 10 cm3 of dichloromethane. The filtrate is concentrated using a rotary evaporator under reduced pressure (5 kPa). The oil obtained is dissolved in 80 cm3 of methanol. 0.757 g of sodium borohydride is added in 3 lots. The reaction mixture is stirred for 1 h at 20° C., then 0.757 g of sodium borohydride is again added. This operation is carried out twice. After stirring at 20° C. for 20 h, the reaction mixture is concentrated using a rotary evaporator under reduced pressure (5 kPa). The concentration residue is taken up in 100 cm3 of dichloromethane and 50 cm3 of water. The organic phase is washed with 2 lots of 50 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 10.8 g of colorless oil obtained are purified by filtration through a pellet of 150 g of silica with 1 dm3 of an 80% heptane/20% ethyl acetate mixture. After concentrating the fractions under reduced pressure, 9.75 g of N-(2-bromobenzyl)heptan-4-amine are obtained in the form of a colorless clear oil.
Reaction SMILES: FC1(F)[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:28][C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.F[B-](F)(F)F.N1([O:44]C(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.N1CCOCC1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:25]([N:22]1[CH2:23][CH2:24][CH:19]([O:18][C:16]2[CH:17]=[C:12]3[CH:11]=[C:10]([C:8]([N:5]4[CH2:4][CH2:3][O:44][CH2:7][CH2:6]4)=[O:9])[NH:28][C:13]3=[N:14][CH:15]=2)[CH2:20][CH2:21]1)([CH3:27])[CH3:26]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: F[B-](F)(F)F
Solvent: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1
Yield: 70 %

Procedure:
The title compound was synthesized in analogy to example 9, intermediate a), from (1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid hydrochloride (example 13, intermediate b)), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, morpholine and N,N-diisopropylethylamine (7 eq.) in DMF to give the desired product as a yellow solid (70%).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14].[CH2:15]([O:17][SiH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])[CH3:16]>C1(C)C(C)=CC=CC=1>[CH2:15]([O:17][Si:18]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][Si:18]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])[O:17][CH2:15][CH3:16])[CH3:16]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCCCCCCCCCCC=C
Solvent: Cc1ccccc1C
Product: CCO[Si](CCCCCCCCCCCCCC[Si](OCC)(OCC)OCC)(OCC)OCC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 25 g of 1,13-tetradecadiene (Aldrich), 44.4 g of triethoxysilane (Shin-Etsu Silicone) and 0.1 mL of 3% xylene solution of a platinum complex of bis((vinyl dimethyl)disiloxane) was stirred at room temperature in a nitrogen atmosphere for 3 days. The resultant reaction mixture was purified by distillation, to obtain 1,14-bis(triethoxysilyl)tetradecane. Its structure was confirmed by NMR.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:6])[CH2:4][OH:5].O.[OH-].[Na+].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)([O:5][CH2:4][CH:3]1[O:6][CH2:2]1)(=[O:18])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2CO2)cc1
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a solution of 10 g of 3-chloro-1,2-propanediol (0.09 mol) and 40 ml of water, was added dropwise at 24-26° C. 16.6 g of 24% sodium hydroxide (0.1 mol). The solution was stirred for one hour. The solution was cooled and thereto 0.17 g of N,N-dimethylaminopyridine (0.0014 mol) and 17.2 g of p-toluenesulfonyl chloride (0.09 mol) in 50 ml of toluene, and then 16.6 g of 24% sodium hydroxide (0.1 mol) were added under stirring at 0-5° C. And the solution was stirred for one hour. After separation with a separating funnel, the organic layer was washed with 50 ml of 1% hydrochloric acid and 50 ml of water. The excess solvent was removed under vacuo. The chemical purity by HPLC at that time was 98.3%. The residue was recrystallized from isopropyl alcohol/hexane=1/1 (V/V) to give 14.0 g of glycidyl tosylate. Chemical purity: 99.6% (yield: 68%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[CH:25]=[C:24]([C:26]#[N:27])[C:19]([C:20]([O:22]C)=O)=[C:18]([C:28]2[CH:29]=[N:30][N:31]([CH2:33][CH3:34])[CH:32]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CO.[Pd].C(Cl)Cl>[CH2:33]([N:31]1[CH:32]=[C:28]([C:18]2[C:19]3[C:20](=[O:22])[NH:27][CH2:26][C:24]=3[CH:25]=[C:16]([NH:15][C@@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[N:17]=2)[CH:29]=[N:30]1)[CH3:34]
Reactant: CCn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc(C#N)c2C(=O)OC)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a flask containing methyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexyl-amino)-4-cyano-2-(1-ethyl-1H-pyrazol-4-yl)nicotinate (62 mg, 0.132 mmol) in MeOH (2 mL) was added HOAc (1 mL) to give a yellow solution. Palladium on carbon was added (14.08 mg, 0.132 mmol). The flask was evacuated and filled with H2 three times, after which the mixture was stirred vigorously at RT under a H2 atmosphere overnight. The mixture was filtered through Celite, and the solvent was removed in vacuo to give a residue, which was dissolved in DCM (10 mL) and MeOH (10 mL). Potassium carbonate was added and the mixture was stirred for 5 h. The solids were filtered out and the filtrate concentrated to give the title compound (50 mg, 86%). [M+H] calc'd for C23H32N6O3, 441; found, 441.