Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16][C:15]=1[O:21][C:22]1[C:27](=[O:28])[N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:32][CH:31]=2)[C:25]([CH2:44][CH2:45][CH3:46])=[N:24][C:23]=1[CH2:47][CH3:48]>C(OCC)(=O)C>[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16][C:15]=1[O:21][C:22]1[C:27](=[O:28])[N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]3[NH:3][C:4](=[O:7])[O:5][N:43]=3)=[CH:32][CH:31]=2)[C:25]([CH2:44][CH2:45][CH3:46])=[N:24][C:23]=1[CH2:47][CH3:48]
Reactant: CCCc1nc(CC)c(Oc2cnc(C)cc2C)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(Oc2cnc(C)cc2C)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
A mixture of hydroxylammonium chloride (0.49 g), sodium hydrogen carbonate (0.69 g) and dimethyl sulfoxide (6 mL) was stirred at 40° C. for 30 min, 4′-{[5-[(4,6-dimethylpyridin-3-yl)oxy]-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.4 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.2 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.27 g, 60%).
Reaction SMILES: [C:1]([OH:11])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ClN1C(OC)=NC(OC)=NC1.CN1CCOCC1.[CH2:30]([NH:34][C:35]([C@H:37]1[CH2:49][C:48]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][C:40]=2[C@@H:39]([C:50]2[CH:58]=[CH:57][C:53]3[O:54][CH2:55][O:56][C:52]=3[CH:51]=2)[NH:38]1)=[O:36])[CH2:31][CH2:32][CH3:33]>O1CCCC1>[CH2:30]([NH:34][C:35]([C@H:37]1[CH2:49][C:48]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][C:40]=2[C@@H:39]([C:50]2[CH:58]=[CH:57][C:53]3[O:54][CH2:55][O:56][C:52]=3[CH:51]=2)[N:38]1[C:1](=[O:11])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:36])[CH2:31][CH2:32][CH3:33]
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: CCCCNC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@@H](c2ccc3c(c2)OCO3)N1
Agent: COC1=NCN(Cl)C(OC)=N1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCCCNC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@@H](c2ccc3c(c2)OCO3)N1C(=O)C=Cc1ccccc1
Yield: 61.3 %

Procedure:
A mixture of trans-cinnamic acid (376 mg. 2.5 mmol), 2-chloro-3,5-dimethoxy-2,4,6-triazine (500 mg, 2.8 mmol), N-methylmorpholine (0.32 mL, 2.9 mmol), and tetrahydrofuran (20 mL) was stirred without cooling for 1.5 hours. Compound (XI) (1.0 g, 2.5 mmol) was added, then the reaction was stirred for an additional 18 hours. The solvent was evaporated, and the residue was dissolved in ethyl acetate, washed once with 1N hydrochloric acid, once with saturated sodium bicarbonate solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 30% ethyl acetate: 70% hexanes) of the residue provided 800 mg (61%) of Example 11 as a solid: mp 114–117° C.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[CH3:14][C:15]1[O:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[O:27][CH:26]=[C:25]([C:28]4[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=4)[C:24]=3[CH:36]=2)=[N:18][N:19]=1.[Sb](Cl)(Cl)Cl>ClCCl.C(OCC)(=O)C>[F:11][CH2:35][S:34][C:31]1[CH:30]=[CH:29][C:28]([C:25]2[C:24]3[CH:36]=[C:20]([C:17]4[O:16][C:15]([CH3:14])=[N:19][N:18]=4)[CH:21]=[CH:22][C:23]=3[O:27][CH:26]=2)=[CH:33][CH:32]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CSc1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)cc1
Agent: Cl[Sb](Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nnc(-c2ccc3occ(-c4ccc(SCF)cc4)c3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
To a solution of [bis(2-methoxyethyl)amino]sulfur trifluoride (1.38 mL, 7.50 mmol) in dichloromethane (10 mL) was added dropwise a solution of 2-methyl-5-[3-[4-(methylthio)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole (1.61 g, 5.00 mmol) in dichloromethane (15 mL) at room temperature. Antimony (III) chloride (0.0570 g, 0.250 mmol) was added to the solution, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/tetrahydrofuran=1/1) and recrystallized from hexane/ethyl acetate to give the title compound (517 mg, yield 30%) as pale-yellow crystals.
Reaction SMILES: C([O:5][C:6](=[O:23])[C@H:7]([CH2:18][CH2:19][C:20](=[O:22])[NH2:21])[NH:8][C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C.C(N(CC)CC)C.Cl>CN(C)C=O>[C:11]1([CH2:10][C:9]([NH:8][C@H:7]([C:6]([OH:23])=[O:5])[CH2:18][CH2:19][C:20](=[O:22])[NH2:21])=[O:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)[C@H](CCC(N)=O)NC(=O)Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)CC[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reaction time: 0.75 h

Procedure:
As shown in Scheme III (FIG. 3), phenylacetylglutamine 5 (25 mg) from Example 1 was dissolved in dimethylformamide (500 μl), and 2-ethyl 5-phenylisoxazolium-3'-sulfonate 8 (26 mg) was added. The pH of the reaction mixture was adjusted to 9 with triethylamine. After 45 minutes, aminomethylfluorescein hydrochloride 7 (38 mg) was added, and reaction mixture was stirred for an additional 12 hours. After evaporation to dryness, the residue was dissolved in methanol and purified by preparative thin layer chromatography using reversed silica gel and water-methanol-acetic acid (40:60:0.4) as an eluent. The result was 40 mg of the desired PAG/AMF conjugate 9. Mass spectrum (FAB): 608 M+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])=[N:28][CH:29]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cn1)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 112.8 %

Procedure:
2-Nitro-4-(trifluoromethyl)benzoic acid (3.0 g) is suspended in chloroform (25 ml), and thereto are added oxalyl chloride (1.67 ml) and N,N-dimethylformamide (2 drops) followed by stirring at room temperature for 3 hours. The reaction solution is concentrated under reduced pressure, and to the residue is poured chloroform (20 ml) to obtain a suspension. Chloroform (30 ml) is added to 5-chloro-2-aminopyridine (1.56 g) and pyridine (1.55 ml), and the solution is ice-cooled. To the solution is added dropwise the suspension prepared above. The reaction solution is stirred at room temperature for 8 hours and concentrated under reduced pressure. The residue is diluted with ethyl acetate, washed successively with 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and evaporated to remove the solvent under reduced pressure. The resulting residue is suspended into n-hexane, filtered and dried to give N-(5-chloropyridin-2-yl)-2-nitro-4-(trifluoromethyl)-benzamide (4.73 g). APCI-MS M/Z: 346/348[M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:35])([CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11].[C:36](=[O:44])([O:41][CH2:42][CH3:43])[O:37][CH:38]([Cl:40])[CH3:39].C(#N)C>C(OC(C)C)(C)C>[Cl-:40].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:35])([C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)=[CH:21][CH:22]=2)[C:13]1=[O:28])[CH3:11])[CH2:29][NH+:30]1[CH2:34][N:33]([CH:38]([O:37][C:36]([O:41][CH2:42][CH3:43])=[O:44])[CH3:39])[CH:32]=[N:31]1
Reactant: C[C@@H](N1CCN(c2ccc(-n3ccnn3)cc2)C1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCOC(=O)OC(C)Cl
Solvent: CC#N
Solvent: CC(C)OC(C)C
Product: CCOC(=O)OC(C)N1C=N[NH+](C[C@](O)(c2ccc(F)cc2F)[C@@H](C)N2CCN(c3ccc(-n4ccnn4)cc3)C2=O)C1
Product: [Cl-]
Temperature: 85 °C
Reaction time: 60 h
Yield: 27.2 %

Procedure:
To a mixture of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-2-imidazolidinone (100 mg) and 1-chloroethyl ethyl carbonate (1.0 g) was added acetonitrile (0.5 ml), and the mixture was stirred for 60 hours at 85° C. After having been cooled, the mixture was diluted with diisopropyl ether (4 ml), and the resulting powder was collected by filtration. The powder was subjected to ODS column chromatography (eluent: methanol/water=3/2). The eluate was concentrated in vacuo. The residue was dissolved in water (10 ml) and lyophilized to give 1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-[1-(ethoxycarbonyloxy)ethyl]-1H-1,2,4-triazolium chloride(Compound 6, 36 mg) as a white powder.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[C:6]([N:16]1[CH2:19][CH:18]([C:20]2[CH:36]=[CH:35][C:23]([NH:24][C:25]([O:27][CH2:28][C:29]3C=CC=CC=3)=[O:26])=[CH:22][C:21]=2[F:37])[CH2:17]1)([O:8][CH2:9][C:10]1[CH:15]=CC=CC=1)=[O:7].C1C[O:41][CH2:40]C1>CCCCCC>[C:6]([N:16]1[CH2:19][CH:18]([C:20]2[CH:36]=[CH:35][C:23]([N:24]3[CH2:29][C@H:28]([CH2:40][OH:41])[O:27][C:25]3=[O:26])=[CH:22][C:21]=2[F:37])[CH2:17]1)([O:8][CH2:9][C:10]1[CH:15]=[CH:4][CH:3]=[CH:2][CH:1]=1)=[O:7]
Reactant: C1CCOC1
Reactant: [Li]CCCC
Reactant: O=C(Nc1ccc(C2CN(C(=O)OCc3ccccc3)C2)c(F)c1)OCc1ccccc1
Solvent: CCCCCC
Product: O=C(OCc1ccccc1)N1CC(c2ccc(N3C[C@H](CO)OC3=O)cc2F)C1
Reaction time: 2 h

Procedure:
n-Butyllithium (5.25 mL of a 1.6 M solution in hexane, 8.40 mmol) was added dropwise to a stirred solution of N-carbobenzyloxy-3-(N-carbobenzyloxy-3-fluoroanilin-4-yl)azetidine (Example 81, Step 4, 3.63 g, 8.36 mmol) at -78° under nitrogen in dry THF (30 mL), then stirred for 2 hr. A solution of R-glycidyl butyrate (1.21 g, 8.40 mmol) in dry THF (3.0 mL) was added and the cooling bath removed after 15 min. After 18 hr, the solvent was removed and the residue partitioned between ethyl acetate (150 mL) and saturated ammonium chloride solution (50 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and evaporated leaving an amber oil. Chromatography over silica gel (150 g, 40-60 lim) eluting with 2-5% methanol-chloroform gave the title compound as a sticky foam. FAB-HRMS: theory 401.1513 (M+1); meas 401.1521.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH2:25][CH3:26])[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:12]3=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]3[N:10]=2)=[CH:6][C:5]([C:32]#[N:33])=[CH:4][C:3]=1[N:34]1[CH2:39][CH2:38][C@@H:37]([NH:40][C:41](=[O:44])[O:42][CH3:43])[C@H:36]([OH:45])[CH2:35]1.[C:46]([O:50][P:51]([O:58][CH2:59][CH2:60][CH2:61][C:62](O)=[O:63])([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])([CH3:49])([CH3:48])[CH3:47].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:46]([O:50][P:51]([O:58][CH2:59][CH2:60][CH2:61][C:62]([O:45][C@H:36]1[C@H:37]([NH:40][C:41]([O:42][CH3:43])=[O:44])[CH2:38][CH2:39][N:34]([C:3]2[CH:4]=[C:5]([C:32]#[N:33])[CH:6]=[C:7]([NH:8][C:9]3[N:14]=[C:13]([N:15]([CH2:25][CH3:26])[CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[C:12]4=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]4[N:10]=3)[C:2]=2[Cl:1])[CH2:35]1)=[O:63])([O:53][C:54]([CH3:55])([CH3:56])[CH3:57])=[O:52])([CH3:49])([CH3:48])[CH3:47]
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Reactant: CC(C)(C)OP(=O)(OCCCC(=O)O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](OC(=O)CCCOP(=O)(OC(C)(C)C)OC(C)(C)C)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To a suspension of methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (100 mg, 0.158 mmol) and 4-((di-tert-butoxyphosphoryl)oxy)butanoic acid (141 mg, 0.475 mmol) in DCM (5 mL) at 0° C., was added DCC (98 mg, 0.475 mmol) followed by DMAP (1.936 mg, 0.016 mmol) and stirred at room temperature for overnight. After completion of the starting material (by LC-MS), reaction mixture was diluted with DCM (2 mL) and filtered through celite and filtrate was washed with water and brine. Combied organic extracts were dried over anhydrous Na2SO4, concentrated. The resultant residue was purified by flash chromatography on silica gel using an ISCO system (eluted with 7:3 Hexanes and EtOAc) to afford (3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4 (ethyl(4-methoxybenzyl)amino)imdazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 4-((di-tert-butoxyphosphoryl)oxy)butanoate (72 mg) as pale yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH3:15][C:16]1[C:17]([C:27](Cl)=[O:28])=[N:18][N:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:27]([C:17]1[C:16]([CH3:15])=[N:20][N:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:18]=1)=[O:28]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: Cc1nn(-c2ccccc2)nc1C(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nn(-c2ccccc2)nc1C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Yield: 61.8 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0454 g, 0.193 mmol), 5-methyl-2-phenyl-2H-1,2,3-triazole-4-carbonyl chloride (0.044 g; 0.193 mmol), and triethylamine (0.0676 mL; 0.481 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 2 to 16% of ethyl acetate in dichloromethane gave 0.0453 g (62%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-methyl-2-phenyl-2H-1,2,3-triazole-4-carboxamide as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][NH2:8].CCN(C(C)C)C(C)C.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(Cl)Cl.CN([CH:32]=[O:33])C>>[Si:22]([O:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][NH:8][C:32]1=[O:33])([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NCCNCCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCCCN1CCNC1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
N-(3-hydroxypropyl)ethylenediamine (19.9 g, 168 mmol), DIPEA (87 mL, 504 mmol, 3.0 eq) were dissolved in 500 mL DMF, followed by the addition of 1,1-carbonyldiimidazole (27.3 g, 168 mmol, 1.0 eq). The reaction was allowed to stir at 50° C. overnight. After overnight, the reaction was cooled to room temperature and TBSCl (25.2 g, 168 mmol, 1.0 eq) was added. The mixture was allowed to stir at room temperature for 3 hours. The reaction was then condensed in vacuo at 40° C. and the obtained residue was then taken into DCM (500 mL). The organic phase was washed with water (2×500 mL) and then with brine (500 mL), dried over MgSO4, filtered and concentrated to afford the title compound as a light yellow solid (42.8 g) in 98% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11]Cl)[S:9][CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:20][NH:21][CH3:22].C(Cl)Cl>CN(C=O)C>[CH3:20][N:21]([CH2:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=1)[CH3:22]
Reactant: CNC
Reactant: CCOC(=O)c1csc(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(CN(C)C)n1
Temperature: 25 °C
Yield: 34.2 %

Procedure:
2-Chloromethyl-thiazole-4-carboxylic acid ethyl ester (500 mg, 2.431 mmol) and potassium carbonate (504 mg, 3.65 mmol) were dissolved in dry DMF. Dimethylamine hydrochloride (218 mg, 2.67 mmol) in dry DMF was added slowly to the reaction mixture and stirred at RT over three nights. DCM was added and the mixture was washed with concentrated NaHCO3 and water. Organic phase was evaporated to dryness and the product was purified by Flash-chromatography. Yield 34.2%. 1H-NMR (400 MHz; CDCl3): δ 1.41 (t, 3H), 2.49 (s, 6H), 3.99 (s, 2H) 4.43 (q, 2H), 8.20 (s, 1H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][S-:13].[Na+].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:12][S:13][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: C[S-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cc(O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.9 %

Procedure:
To a solution of 3-fluoro-4-nitrophenol (3.0 g, 19.1 mmol) in anhydrous DMF (100 mL) was added dropwise sodium thiomethoxide (2.57 mL, 38.2 mmol, 2.0 eq) followed by potassium carbonate (7.92 g, 57.3 mmol, 3.0 eq), and the reaction mixture was stirred at RT for 18 h. Water was then added to quench the solution, and the reaction mixture was extracted with EtOAc (3×250 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, and evaporated under reduced pressure. Purification of the crude using MPLC (biotage) eluted with 20% EtOAc—hexanes afforded 3.25 g (91.9%) of 3-(methylsulfanyl)4-nitrophenol as a yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[F:9][C:10]1[C:16](F)=[CH:15][C:13]([NH2:14])=[C:12]([N+:18]([O-:20])=[O:19])[CH:11]=1.O>O1CCCC1>[F:9][C:10]1[C:16]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:15][C:13]([NH2:14])=[C:12]([N+:18]([O-:20])=[O:19])[CH:11]=1
Reactant: COCCCO
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCCOc1cc(N)c([N+](=O)[O-])cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47.5 %

Procedure:
In a 250 ml three-necked flask under an argon atmosphere, 1 g of 3-methoxy-1-propanol in 20 ml of tetrahydrofuran are cooled to 0° C. using an ice bath and then 450 mg of sodium hydride at 50% in liquid petroleum jelly are introduced in fractions. After stirring for 15 minutes at 0° C., add, over 5 minutes, a solution of 1.5 g of 4,5-difluoro-2-nitroaniline in 20 ml of tetrahydrofuran and then heat in the region of 70° C. for 1 hour 30 minutes. The reaction mixture is poured into 200 ml of water, and extracted with three times 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate and brought to dryness under reduced pressure. After purification by flash chromatography on silica gel (15-20 μm), eluting with a mixture of cyclohexane and ethyl acetate (80/20 by volume), in this way we obtain 1 g of 4-fluoro-5-(3-methoxypropoxy)-2-nitrophenylamine, in the form of a red solid, which is used as it is in the following stage, with the following characteristic:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Cl:21]N1C(=O)CCC1=O>C(#N)C.O>[F:20][C:2]([F:1])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:21])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2C
Solvent: CC#N
Solvent: O
Product: COc1cc2c(cc1Cl)C(C)CN(C(=O)C(F)(F)F)CC2
Temperature: 70 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
A solution of N-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.900 g, 2.67 mmol) in acetonitrile (30 mL) was treated with N-chlorosuccinimide (0.357 g, 2.67 mmol) and stirred overnight at 70° C. The product mixture was diluted with water (100 mL), extracted twice with EtOAc (100 mL), the combined organic phases washed with brine (100 mL), dried with Na2SO4 and concentrated. Flash chromatography (20% EtOAc in hexane, silica) resulted in 0.399 g of a clear oil. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.17 (s, 1H), 6.68 (m, 1 H), 3.88 (s, 3H), 3.78 (m, 1H), 3.6-3.3 (m, 2H), 3.2-2.9 (m, 4H), 1.34 (m, 3H). MS calculated for C14H15ClF3NO2+H: 322, observed: 322.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[S-:12][C:13]#[N:14].[K+].O>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([S:12][C:13]#[N:14])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 88.8 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (16.7 g, 85.8 mmol) in acetic acid (100 mL) was added at room temperature potassium thiocyanate (8.82 g, 90.8 mmol) over 1.5 hr or longer, and the mixture was stirred for 3 hr. The reaction mixture was poured into vigorously stirred water (500 mL), and the mixture was stirred for 30 min. The resulting solid was collected by filtration, and dried to give the title compound (16.5 g, 89%) as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]3[CH2:18][CH2:17][CH2:16][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[I:20]I>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]3[CH2:18][CH2:17][CH2:16][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[I:20])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: II
Reactant: O=C1c2c(Cl)cccc2-n2cncc2[C@@H]2CCCN12
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cccc2-n2cnc(I)c2[C@@H]2CCCN12

Procedure:
27.3 g (100 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one was stirred at 100° for 3 hours with 88 g (350 mmol) of iodine in 200 ml of N,N-dimethylformamide. The reaction mixture was cooled, the separated product was filtered off, rinsed with ethyl acetate and, after drying, there was obtained (S)-8-chloro-11,12,13,13a-tetrahydro-1-iodo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 298°-300°.