Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10]([O:29]C)(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]C.[CH3:31]C(C)([O-])C.[Na+].C(O)(=O)CCCCCCCCCCCCCCCCC>C1(C(C)C)C=CC=CC=1>[C:1]([CH2:2][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]([CH3:31])=[O:29])(=[O:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC
Reactant: CC(C)(C)[O-]
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Solvent: CC(C)c1ccccc1
Product: CC(=O)CCCCCCCCCCCCCCCCCC(=O)c1ccccc1
Yield: 67 %

Procedure:
In a procedure analogous to Example 6, acetophenone was condensed with methyl stearate in cumene using sodium tert-butoxide (15.6 g, 0.163 mol). The acetophenone (15.0 g; 0.125 mol) was added over a period of 28 min, and no methanol was removed from the mixture by distillation. Crude SBM (44.76 g) was obtained. This crude was not purified by crystallization. It was possible, however, to quantitate the amount of SBM present by running a proton NMR spectrum at 54° C. of a sample dissolved in deuterated methanol. The total amount of SBM in the product was 32.65 g, that is, 73% of the sample, corresponding to a yield of 67% for the condensation. The impurities mainly comprised stearic acid and unreacted methyl stearate.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].Cl.[Cl:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Cl>C(OCCOCCO)C.CO>[ClH:13].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: ClCCNCCCl
Reactant: Nc1ccc2ccccc2c1
Agent: Cl
Solvent: CO
Solvent: CCOCCOCCO
Product: c1ccc2cc(N3CCNCC3)ccc2c1
Yield: 57.4 %

Procedure:
A solution of naphthalen-2-amine (2 g, 14 mmol) and bis(2-chloroethyl)amine hydrochloride (2.51 g, 14.1 mmol, 1 eq) in diethylene glycol monoethyl ether (3 mL) was stirred overnight at 149° C. (oil bath). The resulting solution was diluted with methanol (2 ml). The crude product was re-crystallized from diethyl ether to afford 1-(naphthalen-2-yl)piperazine hydrochloride as a yellow solid (2 g, 58%). (ES, m/z): [M+H]+ 213.0
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][CH3:10])[N:4]=[CH:3]1.[C:11]([O:19]CC)(=O)[CH2:12][C:13]([O:15]CC)=O.C1(OC2C=CC=CC=2)C=CC=CC=1.CN1CCCC1=O>>[OH:19][C:11]1[C:12]2[C:13](=[O:15])[N:9]([CH3:10])[CH:5]=[N:4][C:3]=2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=1
Reactant: CNc1cc(=O)n(C)cn1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CN1CCCC1=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cn1cnc2c(c(O)cc(=O)n2C)c1=O
Reaction time: 0.5 h

Procedure:
3-Methyl-6-(methylamino)pyrimidin-4(3H)-one (compound 1B; 400 mg, 2.88 mmol, 1 eq), diethyl malonate (873 μl, 5.76 mmol, 2 eq) and phenyl ether (915 μl, 5.76 mmol, 2 eq) were dissolved in 1-methyl-2-pyrrolidinone (2 ml, 20 mmol). The mixture was placed in a microwave reactor at 240° C. for 30 minutes to yield 5-hydroxy-3,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (compound 1C). The product was confirmed by LC-MS and isolated by HPLC to give 125 mg (21%) of compound 1C. [M+H] calc'd for C9H9N3O3, 208; found, 208.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[CH3:17][C:18]1[NH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][N:22]=1>O>[C:1]1([NH:7][C:8]([N:19]2[C:20]([N+:23]([O-:25])=[O:24])=[CH:21][N:22]=[C:18]2[CH3:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ncc([N+](=O)[O-])[nH]1
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ncc([N+](=O)[O-])n1C(=O)Nc1ccccc1
Reaction time: 4 h
Yield: 82.9 %

Procedure:
A solution of 11.9 g. (0.1 mol.) of phenylisocyanate in 75 ml. of toluene is added dropwise to the stirred suspension of 15.2 g. (0.12 mol.) of 2-methyl-5-nitroimidazole in 60 ml. of water at 10° to 12° C. When the addition is complete, the mixture is stirred for further 4 hours. The separated product is filtered off, washed and dried. 20.4 g. (82.9%) of 1-phenylcarbamoyl-2-methyl-5-nitroimidazole are obtained; m.p.: 218°-220° C.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@H:22]2[C@H:26]([OH:27])[C@H:25]([OH:28])[C@@H:24]([CH2:29][O:30][CH3:31])[O:23]2)=[C:15]([NH:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:14]=1.C(N(CC)CC)C>O1CCCC1>[OH:27][C@@H:26]1[C@H:25]([OH:28])[C@@H:24]([CH2:29][O:30][CH3:31])[O:23][C@H:22]1[N:19]1[CH:18]=[N:17][C:16]2[C:20]1=[N:21][C:13]([CH2:12][NH:11][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])=[N:14][C:15]=2[NH:32][CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCCc4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCCc4ccccc4)nc(CNS(=O)(=O)c4ccccc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
Phenylsulfonylchloride (57 mg, 0.33 mmol) was added to a stirred solution of (2R,3R,4S,5R)-2-[2-(aminomethyl)-6-(phenethylamino)-9H-purin-9-yl]-5-(methoxymethyl)tetrahydro-3,4-furandiol (150 mg, 0.36 mmol) (preparation 48) and triethylamine (110 mg, 1.08 mmol) in tetrahydrofuran (24 ml). The reaction mixture was stirred for 30 min at room temperature and then the solvent was removed under reduced pressure. The residue was azeotroped with dichloromethane and then purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol (95:5) to give the title compound (180 mg) as a foam. MS: 577 (MNa+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.Cl.[N:34]1([CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:37]3[CH2:38][CH2:39][N:34]([CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])[CH2:35][CH2:36]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: COC(=O)CCN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCN1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (5 mL) was added methyl 3-(piperazin-1-yl)propanoate hydrochloride (44 mg, 0.21 mmol), DIEA (90 mg, 0.70 mmol), HATU (79.2 mg, 0.21 mmol). The resulting solution was stirred at room temperature for 4 h and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (40.0% up to 51.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 40.0% in 2 min); Detector, UV 254/220 nm. This resulted in 56.1 mg (49%) of the formic acid salt of methyl 3-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]propanoate as a light yellow solid. LCMS (Method 25) [M+H]+=617.1, RT=1.51 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.68-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 3.60 (s, 3H), 3.49-3.41 (m, 4H), 2.59 (t, 2H, J=6.4 Hz), 2.51 (t, 2H, J=6.4 Hz), 2.39-2.33 (m, 4H).
Reaction SMILES: [N:1]1([CH2:10][C:11]2[O:15][N:14]=[C:13]([CH3:16])[CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:17](Cl)(=[O:21])[C:18](Cl)=[O:19].[CH3:23][C:24]1[CH:28]=[C:27]([NH2:29])[S:26][N:25]=1.[OH-].[Na+]>C(OCC)C.O1CCCC1.C(N(CC)CC)C>[CH3:23][C:24]1[CH:28]=[C:27]([NH:29][C:17](=[O:21])[C:18]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:1]([CH2:10][C:11]3[O:15][N:14]=[C:13]([CH3:16])[CH:12]=3)[CH:2]=2)=[O:19])[S:26][N:25]=1
Reactant: Cc1cc(Cn2ccc3ccccc32)on1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(N)sn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(Cn2cc(C(=O)C(=O)Nc3cc(C)ns3)c3ccccc32)on1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 5-(1H-1-indolylmethyl)-3-methylisoxazole (212 mg, 1.0 mmol) in 10 mL diethyl ether was added to oxalyl chloride (254 mg, 2.0 mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 3 hours and then the reaction solvent was evaporated. The residue was dissolved in 5 mL tetrahydrofuran and then the 3-methyl-5-isothiazolamine (114 mg, 1.0 mmol) and triethylamine (1 mL) in 10 mL tetrahydrofuran was added dropwise. The mixture was stirred for 10 hours and then 1 N NaOH (4 mL) was added to the reaction flask dropwise. The mixture was extracted three times with a total of 60 mL of tetrahydrofuran, the organic phase was dried using anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuum. The residue was crystallized from methanol. Yield: 0.27 g, 71%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:46][C:47]1([CH3:55])[O:52][CH2:51][CH:50]([CH2:53]O)[CH2:49][O:48]1>C(Cl)Cl>[CH3:46][C:47]1([CH3:55])[O:52][CH2:51][CH:50]([CH2:53][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:5]3)[CH2:49][O:48]1
Reactant: COC(=O)c1cc2cc(O)ccc2[nH]1
Reactant: CC1(C)OCC(CO)CO1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc2cc(OCC3COC(C)(C)OC3)ccc2[nH]1
Reaction time: 8 h
Yield: 93.9 %

Procedure:
Methyl 5-Hydroxy-1H-indole-2-carboxylate (0.10 g, 0.5 mmol), triphenylphosphine (0.28 g, 1.0 mmol), diethyl azodicarboxylate (0.18 g, 1.0 mmol) and (2,2-dimethyl-1,3-dioxan-5-yl)methanol (0.15 g, 1.0 mmol) were dissolved in CH2Cl2 (5 mL) and the mixture was stirred overnight. The solvent was evaporated. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were neutralized with saturated NaHCO3 and extracted with EtOAc. The organic extracts were combined dried over Na2SO4, filtered and evaporated to afford the title compound (0.15 g, 90%) as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.74 (br. s., 1H), 7.29 (d, 1H), 7.09 (d, 1H), 7.01 (d, 1H), 6.88 (dd, 1H), 3.92-4.01 (m, 4H), 3.81 (s, 3H), 3.72 (dd, 2H), 1.97-2.08 (m, 1H), 1.31 (s, 3H), 1.28 (s, 3H). MS: m/z 342.2 (M+23).
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][C:8](=[O:10])[NH:7][C:6]1=[O:11])[CH2:2][CH2:3][CH3:4].N([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=C=O.C[N:23]([CH:25]=[O:26])C>>[CH2:1]([N:5]1[CH2:9][C:8](=[O:10])[NH:7][C:6]1=[O:11])[CH2:2][CH2:3][CH3:4].[CH2:15]([C:25]([NH2:23])=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCN=C=O
Reactant: CN(C)C=O
Agent: CCCCN1CC(=O)NC1=O
Product: CCCCCCCC(N)=O

Procedure:
1-Butylimidazolidine-2,4-dione (100 mg, 0.64 mmol) and 1-isocyanatoheptane (108.5 mg, 0.768 mmol) were reacted in DMF in analogy to example 1. Yield: 15 mg (8%), M+H+: 298.18.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].C[OH:5].CC1C=CC(S([O:16][CH2:17][C@H:18]2[O:22][C@@H:21](OC)[C@@H:20]3OC(C)(C)O[C@H:19]23)(=O)=O)=CC=1>C[O-].[Na+]>[CH2:20]([CH2:19][C@@H:18]([OH:22])[C@@H:17]([OH:16])[C@@H:2]([OH:5])[CH:1]=[S:3])[CH3:21]
Reactant: CO
Reactant: CCS
Reactant: CO[C@@H]1O[C@H](COS(=O)(=O)c2ccc(C)cc2)[C@H]2OC(C)(C)O[C@@H]12
Agent: C[O-]
Agent: [Na+]
Product: CCC[C@@H](O)[C@@H](O)[C@@H](O)C=S
Yield: 120.2 %

Procedure:
A solution of ethanethiol (11.5 ml, 155 mmol) in 1N sodium methoxide in methanol (150 ml, 150 mmol sodium methoxide) was added to a solution of methyl 2,3-O-isopropylidene-5-O-p-toluenesulfonyl-β-D-ribofuranoside (50 g, 140 mmol in 200 ml dry methanol) and heated at reflux for 24 h. Solvents were removed by evaporation in vacuo, and the sticky residue was taken up in diethyl ether (300 ml) and washed with water (4×100 ml). The ether phase was dried and concentrated in vacuo to furnish a viscous oil. Fractional distillation (70° C. at 0.06 Torr) using a short-path distillation apparatus afforded 30.0 g (86.5% yield) of methyl 5-deoxy-5-ethylthio2,3-O-isopropylidene-β-D-ribofuranoside (III) as a colorless, viscous oil. TLC (silica; 25% ethylacetate in hexane): Rf 0.44 (III); visualization spray as in A above.
Reaction SMILES: [C:1](=[C:4]([CH:6]([CH2:8][OH:9])O)O)([CH3:3])C.[CH:10]1C=CC=C[CH:11]=1.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:16]([O:9][CH2:8][C:6]1[CH:4]=[CH:1][CH:3]=[CH:11][CH:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccccc1
Reactant: CC(C)=C(O)C(O)CO
Reactant: ClCc1ccccc1
Solvent: O
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
Referring to FIG. 2, the preparation of 1-[12-(m-iodophenyl)-dodecyl]-2-methyl-rac-glycero-3-phosphocholine is described in detail. Isopropylidene glycerol (21.3 g, 161 mmol) was added dropwise into a flame-dried three-necked 200 ml round-bottomed flask containing anhydrous benzene (50 ml) and NaNH2 (6.62 g, 161 mmol) which was equipped with a reflux condenser. The reaction mixture was refluxed under anhydrous conditions for one hour before benzyl chloride (24.0 g, 193 mmol) was slowly added to the hot mixture. The reaction mixture was refluxed overnight. After the reaction mixture had cooled to room temperature, H2O was cautiously added. The benzene layer was removed and washed several times with H2O and dried (MgSO4). The solvent was removed in vacuo to give a dark brown oil which was purified by vacuum distillation to yield pure benzyl ether, rac-1-0-benzyl-2,3-0-isopropylidine glycerol (23.1 g, 79%).
Reaction SMILES: FC(F)(F)C(O)=O.C1(SC)C=CC=CC=1.C([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[NH:53][C:33]3[N:34]=[CH:35][N:36]=[C:37]([O:38][C:39]4[CH:44]=[CH:43][C:42]([NH:45][C:46]([NH:48][CH:49]5[CH2:51][CH2:50]5)=[O:47])=[C:41]([Cl:52])[CH:40]=4)[C:32]=3[CH:31]=2)=[CH:26][CH:25]=1)C1C=CC=CC=1>>[Cl:52][C:41]1[CH:40]=[C:39]([O:38][C:37]2[C:32]3[CH:31]=[C:30]([C:27]4[CH:26]=[CH:25][C:24]([OH:23])=[CH:29][CH:28]=4)[NH:53][C:33]=3[N:34]=[CH:35][N:36]=2)[CH:44]=[CH:43][C:42]=1[NH:45][C:46]([NH:48][CH:49]1[CH2:50][CH2:51]1)=[O:47]
Reactant: O=C(Nc1ccc(Oc2ncnc3[nH]c(-c4ccc(OCc5ccccc5)cc4)cc23)cc1Cl)NC1CC1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Oc2ncnc3[nH]c(-c4ccc(O)cc4)cc23)cc1Cl)NC1CC1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
After adding 2 ml of trifluoroacetic acid and 0.1 ml of thioanisole to 24 mg of 1-{4-[6-(4-benzyloxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-chlorophenyl}-3-cyclopropylurea, the mixture was stirred at 45° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate water was added to alkalinity, and then liquid separation and extraction were performed with ethyl acetate and tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and dried under reduced pressure to obtain 15 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH:10]=[CH:9]1.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12]([NH:26][CH2:25][CH2:23][OH:24])[C:11]=2[CH:10]=[CH:9]1
Reactant: NCCO
Reactant: Cc1ccccc1-n1ccc2c(Cl)nc3c(C)cccc3c21
Product: Cc1ccccc1-n1ccc2c(NCCO)nc3c(C)cccc3c21
Temperature: 150 °C

Procedure:
1-(2-methylphenyl)-4-chloro-6-methylpyrrolo [3,2-c]quinoline (306 mg, 1.0 mmol) was dissolved in 10 ml of ethanolamine in a pressure tube and heated at 150° C. for 3 hours. After removal of the reaction solvent under reduced pressure and diluted in 20 ml of methylene chloride, the residue was dried by anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 236 mg of desired compound as solid in 72% of yield.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[S:11][C:10]3=[N:12][CH:13]=[C:14](I)[N:9]3[N:8]=2)=[CH:4][CH:3]=1.[OH:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.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.ClCCl>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[S:11][C:10]3=[N:12][CH:13]=[C:14]([C:22]4[CH:23]=[CH:24][C:19]([OH:18])=[CH:20][CH:21]=4)[N:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: Fc1ccc(Oc2nn3c(I)cnc3s2)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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Oc1ccc(-c2cnc3sc(Oc4ccc(F)cc4)nn23)cc1
Temperature: 140 °C
Yield: 26.9 %

Procedure:
2-(4-Fluoro-phenoxy)-5-iodo-imidazo[2,1-b][1,3,4]thiadiazole (0.15 g, 0.42 mmol) was suspended in 1,4-dioxane (1.5 mL) at room temperature and argon was bubbled into the mixture while tetrakis(triphenylphosphine)palladium(0) (48 mg, 0.042 mmol), 4-hydroxyphenylboronic acid (66 mg, 0.48 mmol), cesium carbonate (271 mg, 0.83 mmol) and water (1.5 mL) were added. The mixture was deoxygenated for 10 minutes and heated under microwave irradiation at 140° C. for 20 minutes. On cooling, the mixture was diluted with dichloromethane (7 mL), adsorbed in silica and purified by column chromatography (Biotage™/Flash, silica, methanol:dichloromethane 0.2:9.8 to 1.5:7.5). The product obtained was treated with dichloromethane (5 mL) and filtered to give 4-[2-(4-fluoro-phenoxy)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-phenol as a white solid (37 mg, 27% yield).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([OH:34])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:30])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][C@H:36]4[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:38][CH2:37]4)=[O:34])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c14) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow foam.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16](=[O:18])[CH3:17])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Yield: 61 %

Procedure:
3.0 g (12.04 mmol) of the product prepared in step 8.1 in 40 mL of ethyl acetate are placed in a hydrogenation autoclave, and 0.15 g of 10% palladium-on-charcoal are added, under an inert atmosphere. The mixture is stirred at a hydrogen pressure of 5 bar at room temperature. After filtering through Celite and evaporating under reduced pressure, 1.6 g of the expected product are obtained in the form of a beige-coloured solid, which is used as obtained in the following step. Yield=61%.
Reaction SMILES: [C:1]([C:3]1[CH:49]=[CH:48][C:6]2[N:7]([CH2:35][C:36]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:39]=[CH:38][C:37]=3[O:46][CH3:47])[C:8](=[O:34])[C@@H:9]([NH:20][C:21](=[O:33])[C@@H:22]([N:24](C)[C:25](=O)OC(C)(C)C)[CH3:23])[C@H:10]([CH3:19])[N:11]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=2[CH:4]=1)#[N:2].[ClH:50]>O1CCOCC1.CCOCC>[ClH:50].[C:1]([C:3]1[CH:49]=[CH:48][C:6]2[N:7]([CH2:35][C:36]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:39]=[CH:38][C:37]=3[O:46][CH3:47])[C:8](=[O:34])[C@@H:9]([NH:20][C:21](=[O:33])[C@@H:22]([NH:24][CH3:25])[CH3:23])[C@H:10]([CH3:19])[N:11]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[C:5]=2[CH:4]=1)#[N:2]
Reactant: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2cc(C#N)ccc21
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(OC)ccc3ccccc23)c2ccc(C#N)cc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Yield: 83 %

Procedure:
A rt solution of tert-butyl(S)-1-((3S,4S)-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (55 mg, 79.5 μmol) in 4 M HCl in dioxane (398 μl) was stirred for 1 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (41.6 mg, 83%) as a white solid. MS m/z 592 (MH)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][C:6](OS(C)(=O)=O)([C:8]1[C:17]2[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1)[CH3:7].CN(C=O)C>C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>[N:1]([C:6]([C:8]1[C:17]2[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1)([CH3:7])[CH3:5])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cccc2c(C(C)(C)OS(C)(=O)=O)ncnc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc2c(C(C)(C)N=[N+]=[N-])ncnc12
Reaction time: 96 h

Procedure:
Sodium azide (492 mg, 7.57 mmol) is added to methanesulfonic acid 1-methyl-1-(8-methyl-quinazolin-4-yl)-ethyl ester (680 mg, 78% content, 1.89 mmol) in DMF (1.5 mL, 19.56 mmol) and stirring is continued for 4 d. The reaction mixture is diluted with saturated Na2CO3 and EtOAc. The organic layer is washed with brine, dried and filtered to give 4-(1-azido-1-methyl-ethyl)-8-methyl-quinazoline (as a solution in EtOAc).