Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[C:18]([Cl:33])[CH:17]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7]1.C(N(CC)CC)C.[CH3:41][S:42]([CH2:45][CH2:46][O:47][C:48](ON1C(=O)CCC1=O)=[O:49])(=[O:44])=[O:43].C(=O)([O-])O.[Na+]>ClCCl>[Cl:33][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:14]3[N:6]([CH2:5][CH2:4][NH:3][C:48](=[O:49])[O:47][CH2:46][CH2:45][S:42]([CH3:41])(=[O:44])=[O:43])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1
Reactant: CS(=O)(=O)CCOC(=O)ON1C(=O)CCC1=O
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)CCOC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
5-(2-Aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (64.1 mg) and triethylamine (1.0 mL) were dissolved in dichloromethane (5.0 mL), 1-({[2-(methylsulfonyl)ethoxy]carbonyl}oxy)pyrrolidine-2,5-dione (45.6 mg) was added, and the mixture was stirred at room temperature for 2 hrs. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→ethyl acetate:methanol=95:5). Crystallization from diethyl ether/hexane gave the title compound (61.0 mg).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][C:6]2[CH2:7][CH:8]3[CH2:16][N:15](C(OCC4C=CC=CC=4)=O)[CH2:14][CH2:13][N:9]3[S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[H][H]>CO.[Pd]>[F:29][C:2]([F:1])([F:30])[C:3]1[CH:28]=[CH:27][C:6]2[CH2:7][CH:8]3[CH2:16][NH:15][CH2:14][CH2:13][N:9]3[S:10](=[O:11])(=[O:12])[C:5]=2[CH:4]=1
Reactant: O=C(OCc1ccccc1)N1CCN2C(Cc3ccc(C(F)(F)F)cc3S2(=O)=O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=S1(=O)c2cc(C(F)(F)F)ccc2CC2CNCCN21
Reaction time: 1 h

Procedure:
To a solution of phenylmethyl 3,4,11,11a-tetrahydro-8-(trifluoromethyl)pyrazino[1,2-b][1,2]benzothiazine-2(1H)-carboxylate 6,6-dioxide (59.0 mg, 0.134 mmol) in methanol (2 mL) under a nitrogen atmosphere was added 10% Pd—C (6 mg). The nitrogen atmosphere was exchanged for hydrogen (provided by a balloon) using 3 pump/purge cycles. The reaction was stirred for 1 h. The hydrogen atmosphere was exchanged for nitrogen and the reaction was filtered through Celite® AFA. The pad was rinsed with methanol (1 mL). The combined filtrates were concentrated in vacuo to provide the title compound: LCMS (pos. ion spectrum) m/z 307.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:12](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.O>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:10]#[N:12])[CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(Br)n1
Reactant: CCN(CC)CC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.6 %

Procedure:
To a solution of (6-Bromo-pyridin-2-yl)-methanol (20.0 g, 106.37 mmol) in N,N-dimethylformamide (200 mL) at 0° C. was added triethylamine (22.2 mL, 159.55 mmol) followed by methanesulfonyl chloride (9.24 mL, 117.01 mmol). The reaction was allowed to stand for 3 hours at which time the reaction was deemed complete. Water was added to the mixture and the entire mixture was extracted with a mixture of 1:1 AcOEt/Hexanes. The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The crude material (23400 mg) was dissolved in acetonitrile (50 mL) and potassium cyanide (8311 mg, 127.64 mmol) and 18-crown-6 (14057 mg, 53.18 mmol) were added to the solution. The mixture was heated at reflux for 5 h then cooled to room temperature. The volatiles were removed under reduced pressure and the crude material was dissolved in AcOEt and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and the solvents were removed under reduced pressure. The crude residue was purified by column chromatography eluted with a gradient of 10 to 60% AcOEt/hexanes to give (6-Bromo-pyridin-2-yl)-acetonitrile as a brown solid (12290 mg, 59%). MS ES (MH+ 197.1/199.1).
Reaction SMILES: Cl.[F:2][C:3]1[N:8]=[C:7]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28].O>CN(C=O)C>[CH3:28][O:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24][N:13]1[CH:14]=[C:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([F:2])[N:8]=2)[C:10](=[O:16])[NH:11][C:12]1=[O:15]
Reactant: COC(CCBr)OC
Reactant: O=c1[nH]cc(-c2cccc(F)n2)c(=O)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCn1cc(-c2cccc(F)n2)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
A mixture of 5-(6-Fluoro-pyridin-2-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep75, 200 mg, 0.82 mmol), and K2CO3 (169 mg, 1.23 mmol) in DMF (4 ml) was stirred 1 hour at room temperature. 3-Bromo-1,1dimethoxy-propane (165 mg, 0.90 mmol) was added and stirring was continued for 48 hours. Water (50 ml) was added and the product was extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated. The crude was triturated with iPr2O to give 179 mg of the final compound as a white solid (70% yield).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:18]([O:20][CH3:21])=[O:19].Cl>C1COCC1.C(OCC)C>[CH3:21][O:20][C:18]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:19]
Reactant: COC(=O)Cl
Reactant: NCCc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a stirred solution of phenethylamine (75.2 mL, 0.6 mol) and triethylamine (83 mL, 0.6 mol) in THF (500 mL) was added slowly methyl chloroformate 46.2 mL, 0.6 mol) dissolved in THF (50 mL). After the reaction was stirred for an additional 1 h at room temperature, diethyl ether (2 L) and 1N HCl (800 mL) were added. The organic layer was washed with water, dried (MgSO4), filtered, and the filtrate was concentrated in vacuo to give a clear oil of pure title compound (102 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1.C(S(C1[CH:22]=[CH:23][C:24](OC)=[C:25]([C:27]2[NH:28][CH:29]=CC=2)C=1)(=O)=O)C>>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[NH:12][C:13]([CH2:29][N:28]2[CH2:27][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:14][CH:15]=1
Reactant: COc1cccc(-c2ccc[nH]2)c1OC
Reactant: CCS(=O)(=O)c1ccc(OC)c(-c2ccc[nH]2)c1
Product: COc1cccc(-c2ccc(CN3CCCCC3)[nH]2)c1OC

Procedure:
This compound was prepared by a method analogous to that used to prepare example 2, but using 2-(2,3-dimethoxyphenyl)-1H-pyrrole (prepared according to the method of Kruse et al., [Heterocycles, 26, 3141, 1987] from the corresponding acid chloride) in place of 2-(5-ethylsulphonyl-2-methoxyphenyl)-1H-pyrrole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[OH:13][C@:14]([CH3:50])([CH2:48][OH:49])[C:15](=[O:47])[C@@H:16]([NH:24][C:25](=[O:46])[C@@H:26]([NH:30][C:31](=[O:45])[C@@H:32]([NH:36][C:37]([C:39]1[S:43][C:42]([CH3:44])=[N:41][CH:40]=1)=[O:38])[CH2:33][O:34][CH3:35])[CH2:27][O:28][CH3:29])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:1][C:2]1[CH:3]=[C:4]([S:9]([O:49][CH2:48][C@:14]([OH:13])([CH3:50])[C:15](=[O:47])[C@@H:16]([NH:24][C:25](=[O:46])[C@@H:26]([NH:30][C:31](=[O:45])[C@@H:32]([NH:36][C:37]([C:39]2[S:43][C:42]([CH3:44])=[N:41][CH:40]=2)=[O:38])[CH2:33][O:34][CH3:35])[CH2:27][O:28][CH3:29])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CO
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)COS(=O)(=O)c1ccc(F)c(F)c1

Procedure:
Prepared according to procedures described above, by reacting 3,4-difluorobenzenesulfonyl chloride with N—((S)-1-(((S)-1-(((2S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide. MS for C31H36F2N4O10S2 m/z: 727 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH2:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:23][C:19]=1[C:20](O)=[O:21].S(Cl)(Cl)=O.CCN(C(C)C)C(C)C>C1COCC1>[C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH:16][C:20](=[O:21])[C:19]3[CH:23]=[C:24]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])[CH:25]=[CH:26][C:18]=3[Cl:17])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1ncnc2c(N)cccc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CC(C)(C)Nc1ncnc2c(NC(=O)c3cc(CNC(=O)C(C)(C)C)ccc3Cl)cccc12
Yield: 79 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(tert-butyl)quinazoline-4,8-diamine (Intermediate-55, 50 mg, 0.23 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-5, 93 mg, 0.34 mmol), thionyl chloride (1 mL), and DIPEA (119 mg, 0.92 mmol) in THF (2 mL) to afford 85 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.11 (s, 1H), 8.69-8.67 (d, J=7.4 Hz, 1H), 8.49 (s, 1H), 8.16-8.13 (m, 2H), 7.58-7.38 (m, 5H), 4.31-4.29 (d, J=5.6 Hz, 2H), 1.55 (s, 9H), 1.12 (s, 9H); MS (m/z): 468.42 (M+H)+.
Reaction SMILES: C[C@H]1[O:7][C@@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3[C@@H](O)C[C@H]([O:24][C@@H:25]4[CH2:30][C@H:29]5[CH2:31][CH2:32][C@H:33]6[C@@:38]7([OH:48])[CH2:39][CH2:40][C@H:41]([C:42]8[CH2:47][O:46][C:44](=[O:45])[CH:43]=8)[C@@:37]7([CH3:49])[C@H:36]([OH:50])[CH2:35][C@@H:34]6[C@@:28]5([CH3:51])[CH2:27][CH2:26]4)O[C@@H]3C)O[C@@H]2C)C[C@H](O)[C@@H]1O.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH3:51][C@@:28]12[C@H:34]3[CH2:35][C@@H:36]([OH:50])[C@:37]4([CH3:49])[C@@H:41]([C:42]5[CH2:47][O:46][C:44](=[O:45])[CH:43]=5)[CH2:40][CH2:39][C@:38]4([OH:48])[C@@H:33]3[CH2:32][CH2:31][C@@H:29]1[CH2:30][C@@H:25]([OH:24])[CH2:26][CH2:27]2.[OH2:7]
Reactant: C[C@H]1O[C@@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3[C@@H](O)C[C@H](O[C@H]4CC[C@@]5(C)[C@H](CC[C@@H]6[C@@H]5C[C@@H](O)[C@]5(C)[C@@H](C7=CC(=O)OC7)CC[C@]65O)C4)O[C@@H]3C)O[C@@H]2C)C[C@H](O)[C@@H]1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2C[C@@H](O)[C@]2(C)[C@@H](C3=CC(=O)OC3)CC[C@]12O
Temperature: 25 °C
Reaction time: 96 h
Yield: 97.6 %

Procedure:
A suspension of 4.7 grams of digoxin in 300 ml of 95% aqueous ethanol containing 4.7 ml of conc. hydrochloric acid was stirred for four days with a bar magnet stirrer at ambient temperature. Crystalline sodium carbonate was added to neutralize the solution. The filtered solution was evaporated to dryness under vacuum resulting in a white semi-solid residue. This was mulled well in 50 ml of water to remove carbohydrates. The air dried product was dissolved in acetone, filtered and the solution was evaporated to dryness. The product was mulled in ethyl ether to yield 2.4 grams of white crystalline digoxigenin hydrate, m.p. 130°-140°. On HPLC in system C the product was homogeneous with a retention time of 15.2 compared with 20.7 min. for digoxin. TLC in system B gave a blue fluorescent spot at Rf 0.64 for digitoxigenin, compared with Rf 0.49 for digoxin.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:9]([CH2:10][N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:8][N:7]([CH2:26][C@@H:27]2[C@H:30]([NH:31][C:32](=[O:68])/[C:33](=[N:47]\[O:48][C:49]3([C:52]([O:54][CH:55]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)[C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[O:53])[CH2:51][CH2:50]3)/[C:34]3[N:35]=[C:36]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[S:37][CH:38]=3)[C:29](=[O:69])[N:28]2[S:70]([OH:73])(=[O:72])=[O:71])[N:6]=1)=[N+]=[N-]>CCOC(C)=O.CCO.[Pd]>[NH2:1][CH2:4][C:5]1[C:9]([CH2:10][N:11]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:8][N:7]([CH2:26][C@@H:27]2[C@H:30]([NH:31][C:32](=[O:68])/[C:33](=[N:47]\[O:48][C:49]3([C:52]([O:54][CH:55]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[C:62]4[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=4)=[O:53])[CH2:51][CH2:50]3)/[C:34]3[N:35]=[C:36]([NH:39][C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[S:37][CH:38]=3)[C:29](=[O:69])[N:28]2[S:70]([OH:73])(=[O:71])=[O:72])[N:6]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2nc(CN=[N+]=[N-])c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n2)cs1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2nc(CN)c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n2)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2R,3S)-2-((4-(azidomethyl)-5-((bis(tert-butoxycarbonyl)amino)methyl)-2H-1,2,3-triazol-2-yl)methyl)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidine-1-sulfonic acid (111 mg, 0.11 mmol) in EtOAc (1.1 mL) and EtOH (0.22 mL) under N2 was added Pd—C (22 mg, 0.021 mmol). The system was evacuated and backfilled with H2 (3×). After stirring at rt for 4 h, the reaction mixture was filtered through celite with EtOAc and EtOH wash. The filtrate was concentrated in vacuo to afford the title compound (assumed quantitative). The crude residue was used as such in the following step. LCMS: Rt=1.06 min, m/z=1025.7 (M+1), Method 2m_acidic.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:11]([C:12]2[S:13][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][C:19]=3[N:20]=2)[N:10]=[C:9]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[S:8]1)=[N+:2]=[N-:3].C=O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCCl>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:11]([C:12]2[S:13][C:14]3[CH2:15][N:16]([CH3:37])[CH2:17][CH2:18][C:19]=3[N:20]=2)[N:10]=[C:9]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[S:8]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nc2c(s1)CNCC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCCN=[N+]=[N-])c3ccccc3)sc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a solution of 2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (0.050 g, 0.100 mmol) in 1 mL DCE was added formaldehyde (0.033 g, 37 wt % in water, 0.401 mmol) followed by sodium triacetoxyborohydride (0.023 g, 0.110 mmol). The resulting suspension was stirred vigorously at room temperature overnight then was treated with saturated Na2CO3 solution (10 mL) and stirred for 10 minutes. The mixture was extracted with EtOAc (3×10 mL) and the combined organic phases were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (0-3% MeOH/DCM) to afford the desired product as a yellow foam (0.046 g, 89%).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:18]([O-])([O-])([O:20][CH3:21])[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[OH:1][CH2:2][CH:3]1[CH2:5][O:6][C:18]([O:20][CH3:21])([CH3:19])[O:4]1
Reactant: OCC(O)CO
Reactant: COC(C)([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC1(C)OCC(CO)O1
Reaction time: 18 h
Yield: 97 %

Procedure:
A 1-liter round-bottomed flask equipped with a pressure equalizing addition funnel was flushed with nitrogen and charged with 41.5 grams (451 mmol.) of glycerol, 750 ml. of methylene chloride and 100 mg. of p-toluenesulfonic acid. Methyl orthoacetate, 56.9 grams (473 mmol.), was added over 5 minutes at room temperature, with stirring; stirring was continued for 18 hours after which 1 gram of anhydrous sodium carbonate was added and the mixture was stirred for one additional hour and filtered. The solvent was stripped under vacuum to yield 65 grams (97% of theoretical) of 4-hydroxymethyl-2-methoxy-2-methyl-1,3-dioxolane as a clear oil. Its molecular structure was confirmed by proton and carbon-13 nuclear magnetic resonance spectroscopy.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=O)[NH:2]2.[N:9]1[O:10][N:11]=[C:12]2[CH:17]=[C:16]([C:18](Cl)=[O:19])[CH:15]=[CH:14][C:13]=12.O.S(=O)(=O)(O)O>C1COCC1.ClCCl.[Pd]>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][N:2]2[C:18]([C:16]1[CH:15]=[CH:14][C:13]2=[N:9][O:10][N:11]=[C:12]2[CH:17]=1)=[O:19]
Reactant: O=C1NC2C=CC1C2
Reactant: O=C(Cl)c1ccc2nonc2c1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccc2nonc2c1)N1CC2CCC1C2
Reaction time: 18 h

Procedure:
10% Pd/C (0.25 g) was added to a solution of 2-azabicyclo[2.2.1]hept-5-en-3-one in THF (30 ml) and dichloromethane (30 ml) and the mixture hydrogenated at room temperature for 18 h. The solids were filtered off, the solvent evaporated under vacuum, the residue dissolved in THF (60 ml) and lithium aluminum hydride (2 g) added slowly. The mixture was refluxed for 1 h and cooled to +5° C. before adding hexane (60 ml) and concentrated sodium hydroxide solution (4 ml). Celite (2 g) was added and the mixture stirred for 1 h before filtering off the solids and washing with THF (10 ml). To the mixture was added triethylamine (3 ml) and a solution of [2,1,3]-benzoxadiazole-5-carbonylchloride (2 g, 11.0 mmol) in dichloromethane (10 ml) and the mixture stirred overnight. Water (100 ml) was added, acidified to pH 2 with sulfuric acid and extracted with ethyl acetate (2×100 ml). The combined organics were washed with saturated sodium bicarbonate solution (100 ml), dried (NaSO4) and evaporated onto silica gel (5 g) and the residue was chromatographed on silica gel eluting with ethyl acetate/hexane (1:1)→(3:1)→(1:0) to give the desired product as white crystals (0.28 g) after crystallization from MTBE/hexane: mp=92-93° C., LC-MS, MH+=244; 1H NMR (300 MHz, CDCl3, rotamers) δ 7.93-7.87 (m, 2H), 7.59-7.54 (m, 1H), 4.79 and 4.17 (s, total 1H), 3.61 and 3.48 (m, total 1H), 3.28 and 3.08 (dd, J=9.3 and 1.5 Hz, total 1H), 2.74 and 2.64 (s, total 1H), 1.90-1.47 ppm (m, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:12](=[O:13])[C:6]2[S:7][CH2:8][CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=[N:3]1.N1C=CC=CC=1.[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>O>[CH3:1][N:2]1[C:12](=[O:13])[C:6]2[S:7][CH2:8][CH2:9][NH:10][CH:11]([C:27](=[O:28])[C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:31][CH:30]=3)[C:5]=2[CH:4]=[N:3]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Cn1ncc2c(c1=O)SCCNC2
Solvent: c1ccncc1
Solvent: O
Product: Cn1ncc2c(c1=O)SCCNC2C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 57.5 °C
Reaction time: 19 h
Yield: 77 %

Procedure:
To a suspension of 0.8 g (4.06 mmol) of 8-methyl-2,3,4,5-tetrahydro-9(8H)-pyridazino[4,5-b][1,5]thiazepinone in 8 ml of anhydrous pyridine 0.99 g (5.33 mmol) of 4-nitrobenzoyl chloride is added, whereafter the suspension is stirred for 18-20 hours at 55-60° C., while adding every 4 hours 0.5 g (2.54 mmol) of 4-nitrobenzoyl chloride. The reaction mixture is poured on 60 ml of icy water and extracted with 3×50 ml of dichloromethane. The organic phase is washed with 2×50 ml of 2 M hydrochloric acid solution, then with 30 ml of saturated sodium hydrogen carbonate solution and 2×60 ml of water. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography. In this way 1.08 g (77%) of the title compound is obtained with a melting point of 230-232° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.[NH2:12][C:13]([NH2:15])=[S:14].C>O.C(O)C>[NH2:15][C:13]1[S:14][CH:2]=[C:3]([C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:12]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=O)C(=O)CBr
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
195 g of ethyl bromoacetylglyoxylate are added dropwise to a solution of 66 g of thiourea in 450 ml of water and 450 ml of ethanol at 5° and after the addition has ended, the mixture is stirred at room temperature for 30 minutes and at 50° for 30 minutes and, after adding active charcoal, the resulting reaction mixture is then filtered. The filtrate is brought to pH 7 by adding sodium bicarbonate solution, whereupon ethyl 2-amino-thiazol-4-ylglyoxylate crystallizes out in crystals of melting point 147°.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[Cl:34])[CH3:6])=[O:4].C(N(CC)CC)C.[C:42]([NH:45][CH:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][C:54](O)=[O:55])[CH2:48][CH2:47]1)(=[O:44])[CH3:43].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:42]([NH:45][CH:46]1[CH2:47][CH2:48][N:49]([CH2:52][CH2:53][C:54]([NH:1][CH2:2][C:3]([N:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]3[C:24]4[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=5)[C:20]=4[CH:19]=[CH:18][CH:17]=3)[C:8]=2[Cl:34])[CH3:6])=[O:4])=[O:55])[CH2:50][CH2:51]1)(=[O:44])[CH3:43]
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Reactant: CC(=O)NC1CCN(CCC(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CCN4CCC(NC(C)=O)CC4)c3Cl)cccc2n1Cc1ccccn1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a stirred mixture of 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide (0.30 g, 0.60 mmol) in anhydrous DMF (15 mL) was added triethyl amine (0.067 g, 0.66 mmol) under nitrogen at 0° C. The mixture was stirred for 30 min and was added 3-(4-acetamidopiperidin-1-yl)propanoic acid (0.257 g, 1.20 mmol) and HBTU (O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate) (0.296 g, 0.78 mmol). The mixture was stirred at room temperature overnight, evaporated, mixed with a saturated brine solution and extracted with ethyl acetate. Evaporation gave a crude oil that was purified using silica chromatography eluting with a gradient of 2% to 30% DCM (dichloromethane)/MeOH/NH4OH (10:1:0.1). After drying at 78° C. under high vacuum, 3-(4-acetamidopiperidin-1-yl)-N-(2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)propanamide, 8, was isolated as a solid (0.23 g, 55%). LCMS (+ESI) 696 (M+1). 1H-NMR (CDCl3, δ ppm): 8.96 (bs, 1H), 8.59 (m, 1H), 7.58 (t, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.27 (m, 1H), 7.19 (t, J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.82 (m, 1H), 5.66 (m, 2H), 5.48 (bd, 1H), 5.28 (s, 2H), 4.20 (s, 3H), 3.85 (m, 2H), 3.54 (dd, J=18, 3.6 Hz, 1H), 3.26 (s, 3H), 2.96 (bd, 2H), 2.62 (m, 2H), 2.37 (m, 2H), 2.14 (m, 2H), 1.97 (s, 3H), 1.96 (m, 3H). Calcd. for C34H39Cl2N7O5+1.4H2O: C, 56.57; H, 5.84; N, 13.58. Found: C, 56.44; H, 5.59; N, 13.48.