Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:9][C:10]1[CH:23]=[CH:22][C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1.[Na]>C(O)C>[Cl:9][C:10]1[CH:23]=[CH:22][C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)Oc1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
20.9 g (0.115 mol) of ethyl 2-bromo-propionate are run over the course of 30 minutes into a hot solution of 23 g (0.1045 mol) of p-(p-chlorophenoxy)-phenol and 2.4 g (0.1045 mol) of sodium in 90 ml of anhydrous ethanol and the mixture is then heated to the reflux temperature for 2 hours. The inorganic salts are removed by filtration and the ethanol is driven off under reduced pressure. After having dissolved the residue in diethyl ether, washed the solution with water, dried the organic phase over dry sodium sulphate and evaporated the solvent, 32.5 g of an orange-coloured oil which is insoluble in water are obtained.
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:9]=[O:10])C.[CH2:11]([C:13]1[NH:17][CH:16]=[C:15]([C:18]#[N:19])[CH:14]=1)[CH3:12].C([O-])(=O)C.[Na+]>ClCCCl>[CH2:11]([C:13]1[NH:17][C:16]([CH:9]=[O:10])=[C:15]([C:18]#[N:19])[CH:14]=1)[CH3:12]
Reactant: CN(C)C=O
Reactant: CCc1cc(C#N)c[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1cc(C#N)c(C=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
POCl3 (3.3 ml, 35.67 mmol) was added to 1,2-dichloroethane (4 ml), then anhydrous DMF (2.75 ml, 35.67 mmol) was added very slowly. The mixture was stirred at room temperature for ˜10 minutes. 5-Ethyl-1H-pyrrole-3-carbonitrile (Intermediate 30, 856 mg, 7.13 mmol) in 1,2-dichloroethane (2 ml) was added dropwise and the mixture was heated at 80° C. for ˜30 minutes. The mixture was cooled to room temperature and sodium acetate (2.5 g/5 ml) was added and the mixture was stirred for 1 h. The brown/black emulsion was extracted with DCM (4×50 ml). The combined organic phase was washed with water (2×50 ml) dried over Na2SO4 and concentrated in vacuo to give the title compound. (819 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[O:4].[OH-].[Na+].S(=O)(=O)(O)O.[CH2:27](O)C>>[CH3:27][C:8]1[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[N:7]=1
Reactant: CCO
Reactant: COC(=O)CCCCCCc1ncsc1C(=O)OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(CCCCCCC(=O)O)c(C(=O)O)s1

Procedure:
The solution of 8 g of crude 2-methyl-4-(6-carbomethoxyhexyl)-thiazole-5-carboxylic acid methylester (VIII, R1 = CH3) in 25 ml of ethanol was treated with 40 ml of 2 N sodium hydroxide solution. The reaction mixture was refluxed for 30 minutes, then acidified with 5 N sulphuric acid under ice-cooling. After extracting the aqueous reaction mixture with 3 × 75 ml of ethyl acetate, the extract was dried over sodium sulphate and evaporated in vacuo. The obtained crude product was recrystallized from a mixture of acetone and n-hexane, affording 5.3 g of 2-methyl-4-(6-carboxyhexyl)-thiazole-5-carboxylic acid (IX, R1 = CH3). M.p.: 147-149° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[NH:14]2)=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[CH3:33][NH:34][CH3:35].C(O)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[NH:14]2)=[C:7]([S:9]([N:34]([CH3:35])[CH3:33])(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CNC
Solvent: CCO
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)N(C)C)NC(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
5-Cyano-2-{(4S)-5-cyano-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (40 mg, 83 μmol) was dissolved in THF (5 ml), a 33% strength solution of dimethylamine in ethanol (37 μl, 208 μmol; 2.5 eq.) was added at room temperature and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Gromsil C-18, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (13.8 mg, 34% of theory).
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>CO>[F:51][C:48]([F:49])([F:50])[O:47][C:44]1[CH:45]=[CH:46][C:41]([CH2:40][CH2:39][C:28]2[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=2)=[CH:42][CH:43]=1
Reactant: FC(F)(F)Oc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: CO
Solvent: C1CCOC1
Product: O=c1[nH]nc(CCc2ccc(OC(F)(F)F)cc2)cc1O

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-((4-(trifluoromethoxy)phenyl)ethynyl)pyridazine (Intermediate 37) except that the solvent mixture used for the hydrogenation was made up of tetrahydrofuran and methanol and the final compound was recrystallised from MTBE and heptane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:11]CCCOC)C.[CH2:18]([O:20][C:21](=O)[C:22]1C=CC=N[C:23]=1[OH:28])C.COCCCBr>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH3:18][O:20][CH2:21][CH2:22][CH2:23][O:28][N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([O:3][CH3:1])=[O:17])[C:6]1=[O:11]
Reactant: CCOC(=O)c1cccnc1O
Reactant: CCOC(=O)c1cccnc1OCCCOC
Agent: [Ag+2]
Agent: COCCCBr
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COCCCOn1cccc(C(=O)OC)c1=O

Procedure:
2-(3-Methoxypropoxy)-nicotinic acid ethyl ester: 2-Hydroxy-nicotinic acid ethyl ester (1.67 g), 3-methoxypropyl bromide (2.3 g) and silver carbonate (1.38 g) in toluene (80 ml) are reacted in accordance with the procedure described by Labaudiniere et al. (J. Med. Chem. 1992, 35, 4315-4324). Purification of the crude product by FC (dichloromethane-methanol-conc. ammonia 95:5:1) yields 1-(3-methoxypropoxy)-3-carbomethoxy-2(1H)-pyridinone (1.1 7 g), Rf (dichloromethane-methanol-conc. ammonia 95:5:1)=0.59, in the form of a pale-yellow oil, as well as the title compound (0.93 g), Rf (dichloromethane-methanol-conc. ammonia 95:5:1)=0.79, in the form of a yellowish oil.
Reaction SMILES: CN1C=C(C2C=CC=C(NC(C3SC4CCCCC=4C=3)=O)C=2C)N=C([O-])C1=O.[Na+].Br[C:31]1[N:36]=[C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([CH:44]([N:50]3[CH2:55][CH2:54][N:53]([CH2:56][CH3:57])[CH2:52][CH2:51]3)[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:40][CH:39]=2)[C:34](=[O:58])[N:33]([CH3:59])[CH:32]=1.[CH3:60][C:61]1[C:66](C2OC(C)(C)C(C)(C)O2)=[CH:65][CH:64]=[CH:63][C:62]=1[NH:76][C:77]([C:79]1[S:83][C:82]2[CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][C:81]=2[CH:80]=1)=[O:78]>>[CH2:56]([N:53]1[CH2:54][CH2:55][N:50]([CH:44]([C:41]2[CH:42]=[CH:43][C:38]([NH:37][C:35]3[C:34](=[O:58])[N:33]([CH3:59])[CH:32]=[C:31]([C:66]4[CH:65]=[CH:64][CH:63]=[C:62]([NH:76][C:77]([C:79]5[S:83][C:82]6[CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][C:81]=6[CH:80]=5)=[O:78])[C:61]=4[CH3:60])[N:36]=3)=[CH:39][CH:40]=2)[C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:51][CH2:52]1)[CH3:57]
Reactant: CCOC(=O)C(c1ccc(Nc2nc(Br)cn(C)c2=O)cc1)N1CCN(CC)CC1
Reactant: Cc1c(NC(=O)c2cc3c(s2)CCCCC3)cccc1C1OC(C)(C)C(C)(C)O1
Agent: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cn(C)c(=O)c([O-])n1
Agent: [Na+]
Product: CCOC(=O)C(c1ccc(Nc2nc(-c3cccc(NC(=O)c4cc5c(s4)CCCCC5)c3C)cn(C)c2=O)cc1)N1CCN(CC)CC1
Yield: 73.2 %

Procedure:
Using the same procedure as described for the preparation of 10, the reaction of ethyl 2-(4-(6-Bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)phenyl)-2-(4-ethylpiperazin-1-yl)acetate (1.33 g) with N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamide (1.26 g) gave a 73% yield (1.39 g) of 45 as a tan foam: mp 168-170° C.; 1H NMR (300 MHz, CDCl3) δ 8.34 (s, 1H), 7.92 (d, 1H, J=7.8 Hz), 7.80 (d, 2H, J=8.7 Hz), 7.54 (s, 1H), 7.39 (d, 2H, J=8.7 Hz), 7.39 (s, 1H), 7.27 (t, 1H, J=8.1 Hz), 7.18 (dd, 1H, J=7.8, 1.2 Hz), 6.74 (s, 1H), 4.14 (m, 2H), 3.91 (s, 1H), 3.60 (s, 3H), 2.87 (t, 2H, J=5.7 Hz), 2.76 (t, 2H, J=5.7 Hz), 2.61 (br s, 8H), 2.32 (s, 3H), 1.88 (m, 2H), 1.77 (m, 4H), 1.17 (t, 3H, J=7.2 Hz), 1.05 (t, 3H, J=7.2 Hz); MS (ESI+) m/z 683 (M+H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:16])([C:9]1C=CC(C)=CC=1)[CH2:7][OH:8].BrCCCCC(C)(C)C(OCC)=O.[Li+].[BH4-].CO>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:16])([CH3:9])[CH2:7][OH:8]
Reactant: Cc1ccc(C(C)(CO)CCCCBr)cc1
Agent: CCOC(=O)C(C)(C)CCCCBr
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(CO)CCCCBr
Yield: 99 %

Procedure:
According to the procedure described for the synthesis of 206e (Ackerley, N. et al. J. Med. Chem. 1995, 38, 1608-1628; Manley, P. W. et al. J. Med. Chem. 1987, 30, 1812-1818), 205c (500.0 g, 2.0 mol) was reacted with LiBH4 (65.0 g, 3.0 mol) and methanol (95.0 g, 3.0 mol) in CH2Cl2 (6.0 L) to afford 206c (417.0 g, 99%) as an oil. 1H NMR (CDCl3): δ 3.38 (t, 2 H, J=7.4), 3.50-3.40 (br. s, 1 H, OH), 3.22 (d, 2 H, J=5.6), 1.85 (qv, 2 H, J=7.4), 1.50-1.35 (m, 2 H), 1.30-1.20 (m, 2 H), 0.85 (s, 6 H). 13C NMR (CDCl3) δ 71.4, 37.5, 34.9, 33.9, 33.4, 23.7, 22.4.
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH:9]([S:15][C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])[CH2:7][S:8][C@H:3]12.CN(C)C=O.[F:31][C:32]([S:35][CH2:36][C:37](O)=[O:38])([F:34])[F:33]>C(N(CC)CC)C>[F:31][C:32]([S:35][CH2:36][C:37]([NH:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH:9]([S:15][C:16]3[NH:17][N:18]=[N:19][N:20]=3)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])[CH2:7][S:8][C@H:3]12)=[O:38])([F:34])[F:33]
Reactant: NC(=O)CCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)CSC(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)CCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CSC(F)(F)F)[C@H]2SC1

Procedure:
A suspension of 3.85 g. (0.01 mol.) of 7-amino-3-[1-(2-carbamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 50 ml. of dry dimethylformamide was treated with 2 ml. of triethylamine and the mixture was stirred for 15 minutes at 25°. The activated ester of trifluoromethylmercaptoacetic acid (2.57 g., 0.016 mol.) was added to the mixture and it was stirred an additional hour. The reaction mixture was evaporated to dryness and water and ethyl acetate were added to the residue. The layers were separated, ethyl acetate was added to the aqueous phase and it was acidified to pH 2.5 by addition of 6N hydrochloric acid. The mixture was filtered, the layers were separated and the aqueous phase was extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and evaporated to dryness to give the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:32]([O:34][CH:35]([O:42][CH2:43][CH3:44])[C:36]#[C:37][C:38]([O:40][CH3:41])=[O:39])[CH3:33]>C1COCC1.O>[CH2:43]([O:42][CH:35]([O:34][CH2:32][CH3:33])/[C:36](/[O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=1)=[CH:37]/[C:38]([O:40][CH3:41])=[O:39])[CH3:44]
Reactant: CCOC(C#CC(=O)OC)OCC
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(OCC)/C(=C/C(=O)OC)Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
To a solution of 2.43 g (15 mmol) of 4-trifluoromethylphenol in 40 mL of THF was added 1.12 g (20 mmol) of powdered KOH and 5.28 g (20 mmol) of 18-crown-6. The solution was heated to 50° C. for 15 minutes, whereupon 3.73 g (20 mmol) of methyl 4,4-diethoxy-2-butynoate was added. The mixture was stirred for 30 minutes, then allowed to cool to room temperature. The solution was then poured into water, and extracted 3 times with 40 mL of ethyl acetate. The organic layers were combined, dried (MgSO4) and concentrated. The crude oil was subjected to column chromatography on SiO2. Elution with 20% ethyl acetatehexane yielded 2.31 g (65%) of an oil, used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].N1C=CC=CC=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(OCC)(=O)C>[C:20]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:13])(=[O:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCCCO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 97.2 %

Procedure:
To a mixture of tert-butyl 4-hydroxybutylcarbamate (3.83 g) obtained in Reference Example 35 and ethyl acetate (20 mL) were added pyridine (1.80 mL) and acetic anhydride (2.27 g), and the mixture was stirred at room temperature for 19 hrs. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL), an aqueous copper sulfate solution (30 mL), water (30 mL) and saturated brine (30 mL) and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave the title compound (4.55 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:18]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: FC(F)(F)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(Oc2ncccc2C(F)(F)F)cc1
Yield: 82.5 %

Procedure:
2-Chloro-3-trifluoromethylpyridine (1.0 g), methyl 4-hydroxybenzenecarboxylate (838.3 mg) and potassium carbonate (2.28 g) were suspended in acetonitrile (10 mL), and heated under reflux for 27 hours, and then 2-chloro-3-trifluoromethylpyridine (1.0 g) was added thereto and further heated under reflux for 24 hours. Water (100 mL) was added to the reaction liquid, extracted with ethyl acetate (100 mL), and the organic layer was washed with aqueous 2 N sodium hydroxide solution (100 mL), water (100 mL) and saturated saline water (100 mL) in that order, dried with magnesium sulfate and evaporated under reduced pressure to obtain a pale yellow oil. The resulting oil was purified through silica gel column chromatography (hexane/ethyl acetate=8/2) to obtain the entitled compound (1.35 g) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]([OH:24])([C:22]#[CH:23])[CH3:21]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:23]#[C:22][C:20]([OH:24])([CH3:21])[CH3:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)O
Reactant: CN1Cc2c(I)ncn2-c2cccc(Br)c2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CN1Cc2c(C#CC(C)(C)O)ncn2-c2cccc(Br)c2C1=O

Procedure:
3.74 g (8.95 mmol) of 7-bromo-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at the boiling temperature for 1.5 hours with 0.80 g (9.5 mmol) of 2-methyl-3-butyn-2-ol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 30 ml of diethylamine. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After recrystallization of the residue, which remains behind upon evaporation of the eluate, from ethyl acetate there was obtained 7-bromo-4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 207°-208°.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Cl:14][C:15]1[N:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>ClCCl>[Cl:14][C:15]1[N:20]=[CH:19][C:18]([S:21]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Cl)nc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.8 %

Procedure:
A solution of triethylamine (0.27 mL, 1.94 mmol) and morpholine (0.085 mL, 0.97 mmol) in dry dichloromethane (2 mL) was added to a stirred suspension of 6-chloropyridine-3-sulfonyl chloride (0.204 g, 0.96 mmol; described in: Naegeli, C. et al. Helv. Chim. Acta. 1938, 21, 1746-1750) in dry dichloromethane (1 mL). The resulting clear solution was stirred at room temperature for 20 min. The solvent was evaporated and the residue was purified on a silica gel column using dichloromethane/methanol, (97:3), as the eluent to give 0.176 g (70% yield) of the title compound: 1H NMR (DMSO-d6, 400 MHz) δ 8.75 (dd, J=3, 1 Hz, 1H), 8.18 (dd, J=8, 3 Hz, 1H), 7.82 (dd, J=8, 1 Hz, 1H), 3.63 (m, 4H), 2.96 (m, 4H).
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][C:8]([C:9]([NH:11][C:12]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C)C=O>[N+:21]([C:18]1[CH:19]=[CH:20][C:12]2[N:11]=[C:9]([C:8]3[CH:24]=[CH:25][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=3)[O:16][C:14](=[O:15])[C:13]=2[CH:17]=1)([O-:23])=[O:22]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])cc2C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2nc3ccc([N+](=O)[O-])cc3c(=O)o2)cc1
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a suspension of 2-(4-tert-butylbenzoylamino)-5-nitrobenzoic acid (37.1g, 108 mmol) and N,N-dimethylformamide (0.4 mL, 5.4 mmol) in methylene chloride (200 mL) was added oxalyl chloride (10.4 mL, 119 mmol) in a dropwise manner. After stirring for 2 h, the mixture was filtered and the small amount of black solid was discarded. The filtrate was concentrated in vacuo to give 32.9 g (94%) of the title compound as a light brown solid; mp 159-61° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:17]4[CH:18]=[C:19]([O:22]C)[CH:20]=[CH:21][C:16]=4[O:15][CH:14]=3)=[C:9]([CH2:24][CH2:25][CH3:26])[CH:8]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=4[O:15][CH:14]=3)=[C:9]([CH2:24][CH2:25][CH3:26])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1coc2ccc(OC)cc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1coc2ccc(O)cc12
Temperature: 25 °C

Procedure:
To a solution of the product from Step 10 (0.34 g, 0.86 mmol) in dichloromethane (5.0 mL) cooled with an ice bath was added boron tribromide (1.0 M in dichloromethane, 1.7 mL, 1.7 mmol). The reaction mixture was gradually warmed to room temperature over 1 h, diluted with ethyl acetate and poured into a saturated solution of sodium bicarbonate. The organic layer was washed with brine, dried and filtered through a short path of silica gel to give the title product.
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:20][NH2:21]>CS(C)=O>[N:1]1([C:10]2[N:18]=[C:17]([NH:21][CH3:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Reactant: CN
Solvent: CS(C)=O
Product: CNc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Temperature: 120 °C

Procedure:
200 mg of product obtained in stage 1 above are mixed with 2 ml of DMSO and 0.115 ml (5 equivalents) of methylamine, and the mixture is then heated at 120° C. for approximately 18 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 90-9-1 mixture for eluent. Evaporation is carried out and a paste is formed in methylene chloride. Partial drying and drying under vacuum at 50° C. are carried out. 190 mg of expected product are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O)(=[O:11])=[O:10].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:45]1[NH:50][CH2:49][CH2:48][N:47]2[CH2:51][CH2:52][CH2:53][C@H:46]12>CN(C)C(=O)C.CC1CCCO1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([N:50]2[CH2:49][CH2:48][N:47]3[CH2:51][CH2:52][CH2:53][C@@H:46]3[CH2:45]2)=[O:17])[CH:13]=1)(=[O:10])=[O:11]
Reactant: C1C[C@@H]2CNCCN2C1
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2ccccc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC1CCCO1
Solvent: CC(=O)N(C)C
Product: O=C(c1cccc(S(=O)(=O)Nc2ccccc2F)c1)N1CCN2CCC[C@@H]2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid (800 mg, 2.71 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1133 mg, 2.98 mmol) in N,N-dimethylacetamide (6.5 mL) and 2-methyltetrahydrofuran (19.5 mL) was added (R)-octahydropyrrolo[1,2-a]pyrazine (479 mg, 3.79 mmol). The reaction was stirred at room temperature for 3 hours, diluted with 2-methyltetrahydrofuran (5 mL), and washed with saturated bicarbonate (2×25 mL). The combined aqueous layers were adjusted to pH 7 with buffer and re-extracted with 2-methyltetrahydrofuran (3×15 mL). The combined organic layers were concentrated under reduced pressure. The residue was taken up in ethanol (25 mL) and concentrated to give the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[NH:36]1[CH2:39][CH2:38][CH2:37]1.O>C1COCC1>[N:36]1([C:2]2[C:7]([C:8]#[N:9])=[C:6]([C:10]3[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=3)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]3[N:25]=[C:26]([C:29]4[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=4)[S:27][CH:28]=3)[N:3]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: C1CNC1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N2CCC2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At RT, 100 mg (0.19 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.015 ml (0.22 mmol) of azetidine were stirred in 2.5 ml of THF overnight. Another 0.025 ml (0.36 mmol) of azetidine was then added, and the mixture was once more stirred at RT overnight. About 10 ml of water were added to the reaction mixture, and the precipitate formed was filtered off, washed with water and dried under high vacuum. This gave 85 mg (82% of theory) of the desired target compound.