Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15]2=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:35][C:36]#[N:37]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH2:35][C:36]#[N:37])[C:15]2=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: N#CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)n(CC#N)c3ccccc32)CC1
Reaction time: 0.17 h
Yield: 67.4 %

Procedure:
A solution of 4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (2.91 g, 9.16 mmol) in THF (10 mL) was added dropwise to a solution of KHMDS (2.19 g, 11.0 mmol) in THF (20 mL). The mixture was stirred for 10 min then bromoacetonitrile (3.2 mL, 46 mmol) was added. The resulting mixture was stirred for 4 h then partitioned between EtOAc (750 mL) and saturated aqueous NaHCO3 (200 mL). The EtOAc layer was washed with H2O (3×200 mL) and brine (200 mL). The combined washes were extracted with EtOAc (2×150 mL). The combined extracts were dried over Na2SO4 and concentrated. Column chromatography (silica, 20-60% EtOAc/hexanes) afforded 2.20 g (67%) of 4-(3-cyanomethyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester. The purified material was dissolved in CH2Cl2 (40 mL) and diluted with TFA (25 mL). The resulting mixture was stirred for 1 h then diluted with CH2Cl2 (250 mL) and washed with 1 N NaOH (100 mL). The aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined extracts were dried over Na2SO4 and concentrated to 1.59 g (95%) of the title compound which was suitable for further use without purification. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.1. MS (electrospray): m/z calculated for C14H17N4O [M++H] 257.14. found 257.1. 1H NMR (CDCl3, 400 Hz): 733-7.29 (m, 1H), 7.17-7.02 (m, 3H), 4.75 (s, 2H), 4.41 (tt, J=12.2, 4.4 Hz, 1H), 3.28 (br d, J=9.8 Hz, 2H), 3.11 (br s, 1H), 2.80 (t, J=10.0 Hz, 2H), 2.37 (dq, J=12.5, 4.2 Hz, 2H), 1.83 (br d, J=11.8 Hz, 2H).
Reaction SMILES: [NH:1]=[C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[C:4]([CH3:9])[N:3]1[NH2:10].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.C(N(CC)CC)C.Cl[C:32](=[O:40])[CH:33]([CH3:39])[CH2:34][C:35]([O:37][CH3:38])=[O:36]>C(#N)C>[NH2:10][N:3]1[C:4]([CH3:9])=[CH:5][N:6]=[C:7]([CH3:8])/[C:2]/1=[N:1]/[C:32](=[O:40])[CH:33]([CH3:39])[CH2:34][C:35]([O:37][CH3:38])=[O:36]
Reactant: Cc1ncc(C)n(N)c1=N
Reactant: COC(=O)CC(C)C(=O)Cl
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CC(C)C(=O)/N=c1/c(C)ncc(C)n1N
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To a solution of 2-imino-3,6-dimethylpyrazin-1(2H)-amine-2,4,6-trimethylbenzenesulfonate (2 g, 5.92 mmol) in acetonitrile (60 mL) was added triethylamine (1.8 g, 17.76 mmol). The mixture was stirred at 50° C. for 30 min. Methyl 4-chloro-3-methyl-4-oxobutanoate (1.35 g, 8.23 mmol) was added. The mixture was stirred for an additional 10 min. Then the solution was evaporated to give 1.1 g of the crude product as a brown solid. ESI MS: m/z 267 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH2:6][O:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]#[N:5].[C:27](OC(=O)C)(=[O:29])[CH3:28].N1C=CC=CC=1.Cl>C(OCC)(=O)C>[C:27]([O:1][CH:2]([CH2:6][O:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:3][C:4]#[N:5])(=[O:29])[CH3:28]
Reactant: N#CCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(CC#N)COC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To (±)-3-hydroxy-4-trityloxybutane-nitrile (1.03 g, 3.00 mmol) under N2 was added acetic anhydride (1.53 g, 15.00 mmol) and pyridine (0.26 g, 3.30 mmol) and the resultant mixture was stirred overnight at room temperature. After completion of the reaction (TLC) the reaction mixture was diluted with ethyl acetate (25 mL) and treated with 1N HCl (20 mL). The organic layer was separated, washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated and the residue was purified by column chromatography employing EtOAc-hexane (15:85) as eluent to afford the required 3-acetyloxy-4-trityloxybutanenitrile in nearly quantitative yield. IR (KBr) 3466, 3066, 3019, 2925, 2863, 2235, 1741, 1223, 1004 cm−1; 1HNMR (300 MHz, CDCl3) δ 2.09 (s, 3H), 2.76 (d, 2H, J=5.69, 5.79 Hz), 3.92-4.02 (m, 1H), 7.23-7.41 (m, 15H); Mass (EI) 259, 243, 165, 105, 77.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH3:13])([O-:3])=[O:2].[CH2:14]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1CCCC1>CN(C)C=O.C(O)(C)C>[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][C:25](/[CH:26]=[CH:13]/[C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:28][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: C1CCNC1
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(/C=C/c2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
18.21 g (0.1 mol) of 2,4-dinitrotoluene, 21.23 g (0.1 mol) of 4-benzyloxy-benzaldehyde and 1.8 mL of pyrrolidine in 140 mL of dimethylformamide were heated for 2 hours at 100° C. which caused the reaction mixture to assume a dark-brown color. The reaction mixture was then allowed to cool to room temperature after which it was diluted with 210 mL of isopropanol and allowed to agitate for an additional hour with ice cooling. The product was suction-filtered off, washed with a small amount of cold isopropanol and then dried at 40° C. under vacuum.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][CH2:16][C@@H:17]([OH:19])[CH3:18]>>[C@@H:17]([O:19][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([CH2:16][CH3:15])[CH3:18]
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: CC[C@H](C)O
Product: CC[C@H](C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O

Procedure:
Prepared in analogy to Example B4(c) from 2-Fluoro-5-methanesulfonyl-benzoic acid (example B4(b)) and S-(+)-2-butanol. White solid. MS (m/e): 271.1 ([M−H], 100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23]2[CH:28]=[CH:27][N:26]3[N:29]=[CH:30][C:31]([C:32]([O:34]CC)=[O:33])=[C:25]3[N:24]=2)=[CH:16][C:15]([F:37])=[CH:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.CO.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23]2[CH:28]=[CH:27][N:26]3[N:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[C:25]3[N:24]=2)=[CH:16][C:15]([F:37])=[CH:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3NCCNC(=O)OC(C)(C)C)nc12
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of (R)-ethyl 5-(2-(2-(2-(tert-butoxycarbonylamino)ethylamino)-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (38 mg, 0.074 mmol) in THF/MeOH/water (2:2:1, 0.7 mL) was added LiOH—H2O (9.3 mg, 0.22 mmol), followed by stirring at 50° C. for 18 hours. After removal of solvent, the reaction residue was taken up in water (0.5 mL), and acidified with 1 N HCl (0.22 mL) to pH 3. The reaction mixture was extracted with EtOAc (3×2 mL), dried (Na2SO4), filtered and concentrated to give the desired product, which was used in the next step directly without further purification, assuming quantitative conversion. MS (apci) m/z=486.0 (M+H).
Reaction SMILES: C([Si](CC)(CC)[O:4][C@H:5]([CH2:10][CH2:11][CH3:12])[C@@H:6]([CH3:9])[CH2:7][OH:8])C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCOCC>[CH3:9][C@@H:6]([C@H:5]([OH:4])[CH2:10][CH2:11][CH3:12])[CH2:7][OH:8]
Reactant: CCC[C@@H](O[Si](CC)(CC)CC)[C@@H](C)CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Product: CCC[C@@H](O)[C@H](C)CO
Yield: 52 %

Procedure:
Alcohol 24 (100.0 mg, 0.4057 mmol) was dissolved in 2.0 ml of Et2O and treated with 676 mg of tetrabutylammonium fluoride on silica (1.2 mmol/g, 0.8112 mmol, 2.0 eq) and stirred at 25° C. for 3h at which time alumina (acidic, ca. 1 g) was added. The slurry was filtered through a pad of Celite, concentrated and chromatographed (25 g SiO2, 60% CH2Cl2 /40% EtOac) to yield 27.9 mg of diol 26 (52%) which was protected for characterization. Diol 26 (27.9 mg, 0.211 mmol) was dissolved in 5.0 ml of THF, and treated with 2,2-dimethoxypropane (64 μl, 0.5159 mmol, 2.0 eq) and a crystal of p-toluenesulfonic acid. After 67 h at 25° C., 200 mg of Na2CO3 was added. The mixture was poured onto 7.0 ml of 0.10 M pH 7.0 phosphate buffer, extracted with Et2O (3×10 ml), washed with H2O (1×1 ml), 5% NaHCO3 (2×1 ml), brine (1×1 ml), dried over MgSO4 and concentrated to give 30.0 mg of acetonide 28 as a clear liquid (89%). 1H NMR (CDCl3, 360.134 MHz) δ 4.04 (1H,dd,J=11.56, 2.90 Hz), 3.86 (1H,ddd,J=10.40, 5.29, 2.52 Hz), 3.52 (1H,dd,J=11.44, 0.68 Hz), 1.37 (3H, s), 1.33 (3H, s), 1.45-1.1 (5H,m), 0.99 (3H, d,J=6.92 Hz), and 0.86 (3H,t,J=7.08H). 13C NMR (CDCl3, 90.55 MHz) δ:72.0, 71.2, 67.0, 35.0, 31.7, 29.8, 19.1, 18.5, 14.0, and 10.5. IR (thin film): 2957(m), 2924(s), 2855(m), 1732(br), 1458(m), 1377(w), 1262(m), 1179 9(w), 1074(w), and 800(w) cm-1.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([C:22]([OH:24])=[O:23])[CH:13]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl.O>CC(C)=O>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([C:22]([OH:24])=[O:23])[CH:13]=2)[CH2:7][CH2:6]1
Reactant: O=C(O)c1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(Oc2cc(C(=O)O)nc(C(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-(1,4-Dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidine-4-carboxylic acid (0.50 g, 1.4 mmol) was dissolved in acetone (12.8 mL) To this solution was added a solution of 12.0 M hydrogen chloride in water (1.5 mL, 18 mmol) and stirred at RT for 16 hours at which time LCMS showed the reaction was compete. The reaction mixture was extracted with EtOAc and was evaporated to give the product. The crude product was used in the next step. MS (ES): 305(M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][NH:18][C@@H:17]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH2:16]3)[C:12]3[C:11]4[CH:30]=[CH:31][CH:32]=[CH:33][C:10]=4[S:9][C:8]=3[NH:7][C:6]=2[CH:34]=1.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>ClC(Cl)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:35])[C@@H:17]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH2:16]3)[C:12]3[C:11]4[CH:30]=[CH:31][CH:32]=[CH:33][C:10]=4[S:9][C:8]=3[NH:7][C:6]=2[CH:34]=1
Reactant: Fc1ccc(CC[C@H]2CN(C3=Nc4ccc(F)cc4Nc4sc5ccccc5c43)CCN2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CN1CCN(C2=Nc3ccc(F)cc3Nc3sc4ccccc4c32)C[C@@H]1CCc1ccc(F)cc1
Yield: 68.2 %

Procedure:
Using a method similar to the method of Example 543, using (S)-9-fluoro-5-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene (0.339 g, 0.714 mmol), sodium triacetoxyborohydride (0.227 g, 1.07 mmol), and aqueous formaldehyde (0.080 mL, 1.1 mmol) in dichloroethane, and employing a second chromatographic purification, eluting with a gradient of a solution of ethyl acetate: hexane (1:1) with 2% 2M ammonia in methanol (in hexane) added, gives the title compound (0.238 g). Mass spectrum (APCI+, m/e): 489 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[C@:11]([OH:15])([CH3:14])[CH2:12][OH:13])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl>ClCCl.C(OCC)(=O)C>[CH3:28][S:29]([O:13][CH2:12][C@@:11]([OH:15])([CH3:14])[C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:17]([F:19])([F:18])[F:20])[CH:5]=1)=[O:16])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@](O)(CO)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@](O)(COS(C)(=O)=O)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
439 mg of chiral diol (5C) of Example 22 was dissolved in 20 ml of dichloromethane. The solution was cooled to 0° C. (ice). 170 mg of triethylamine was added. 174 mg of methanesulfonyl chloride was dissolved in 5 ml of dichloromethane and slowly added to the diol solution. After the addition was completed, the mixture was allowed to warm to room temperature. After 25 minutes at room temperature, the reaction mixture was analyzed with HPLC; there was still 27% of diol present. Next 70 mg of methanesulfonyl chloride was added. After 10 minutes at room temperature, the reaction was completed. 60 ml of ethyl acetate and 60 ml of 0.5 N aqueous HCl were added. The organic layer was washed subsequently with 60 ml of water and 60 ml of saturated NaHCO3, dried (Na2SO4), filtrated and evaporated to dryness. Purification of the residue by column chromatography (Merck silica gel 60; eluens:ethyl acetate) afforded the title compound as a green/black oil. Isolated yield: 473 mg. 1H-NMR confirmed the expected structure (2S-enantiomer). HPLC: 94% purity.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.CC([Mg]Cl)C.[O:15]=[C:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[NH4+].[Cl-]>C1COCC1>[OH:15][C:16]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: N#Cc1ccc(I)cc1
Reactant: O=C1CCOCC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(O)CCOCC2)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-iodobenzonitrile (5.0 g, 21.8 mmol) in dry THF (100 mL) was added 2-propyl magnesium chloride (2M solution in diethyl ether, 11 mL, 21.8 mmol) dropwise at −40° C. After stirring for 1.5 h at this temperature, the reaction mixture was cooled to −78° C. before it was canulated to a solution of 4-oxotetrahydro-2H-pyrane (3.28 g, 32.8 mmol) in dry THF (100 mL) which was likewise cooled to −78° C. After the slow addition of the Grignard reagent was completed, the reaction mixture was stirred at −78° C. for additional 10 minutes, then at 0° C. for 2 h, and finally at rt for 30 minutes. A few mL saturated aqueous NH4Cl were added, and then most of the solvent was evaporated. The residue was partitioned between water and ethyl acetate (200 mL each). After separation, the aqueous layer was extracted using ethyl acetate. The combined organic layers were successively washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the crude material was purified by MPLC (silica, cyclohexane/ethyl acetate 2:1→1:1). The title compound was obtained as a highly viscous oil (1.19 g, 27%): 1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, 2H), 7.70 (d, 2H), 5.30 (s, 1H), 3.81-3.70 (m, 4H), 2.02-1.94 (m, 2H), 1.51-1.48 (m, 2H); DCI(NH3)-MS m/z 204 (MH)+, 221 (M+NH4)+; HPLC RT (Method I) 3.35 min.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH3:39])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[Cl:46]Cl>O1CCOCC1>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH2:39][Cl:46])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCl
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C=C(CCl)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 95 %

Procedure:
A 1.0 g quantity of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-methyl-3-butenate was dissolved in 10 ml of dioxane. To the solution was added 3 g of NaHCO3 and the mixture was stirred at room temperature. Into the reaction mixture was forced 1.5 equivalents of chlorine gas and the mixture was stirred for 2 hours. The same subsequent procedure as in Example 4 was conducted, giving 1.0 g of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-chloromethyl-3-butenate in 95% yield.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:25][C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:31]1(Br)[CH2:35][CH2:34][CH2:33][CH2:32]1.[H-].[Na+]>CN(C=O)C>[CH:31]1([N:28]2[CH:27]=[C:26]([CH2:25][N:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=3)[C:11]([CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=4)[CH2:16][CH2:15][CH2:14]3)=[O:12])[CH:30]=[N:29]2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COc1ccc2c(c1)C(C(=O)N(Cc1cn[nH]c1)c1ccc(C(C)C)cc1)CCC2
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(C(=O)N(Cc1cnn(C3CCCC3)c1)c1ccc(C(C)C)cc1)CCC2
Reaction time: 0.5 h

Procedure:
N-(4-Isopropylphenyl)-7-methoxy-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.44 g) and cyclopentyl bromide (0.12 mL) were dissolved in DMF (5 mL), and sodium hydride (0.09 g) was added under ice-cooling. The mixture was stirred at the same temperature for 30 min and then at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give N-[(1-cyclopentylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.38 g).
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]([CH3:15])=[C:8]2[C:3]=1[CH:4]([OH:18])[CH2:5][CH2:6][S:7]2(=[O:17])=[O:16].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>N1C=CC=CC=1>[C:19]([O:18][CH:4]1[C:3]2[C:8](=[C:9]([CH3:15])[CH:10]=[C:11]([C:12]([OH:14])=[O:13])[C:2]=2[CH3:1])[S:7](=[O:16])(=[O:17])[CH2:6][CH2:5]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC2O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC2OC(=O)c1ccccc1

Procedure:
1.0 g (4.1 mmol) of 5,8-dimethyl-4-hydroxy-1,1-dioxo-1,2,3,4-tetrahydro-1λ6-thiochromene-6-carboxylic acid, 0.58 g (4.1 mmol) of benzoyl chloride and a spatula tip of N,N-4-dimethylaminopyridine was stirred in 10 ml of pyridine overnight. The mixture was subsequently poured onto 5 M HCl in crushed ice and extracted with ethyl acetate. The organic phase was washed with 1 M HCl (2×20 ml) and sat. NaCl solution (2×40 ml), dried over MgSO4 and concentrated using a rotary evaporator.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10](=[O:35])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:19](=[O:28])[C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:12]=1>>[CH3:8][O:9][C:10](=[O:35])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:20](=[C:21]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:19]2=[O:28])[CH:12]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Reactant: Ic1ccccc1
Product: COC(=O)c1cccc(CN2C(=O)C(=C(c3ccccc3)c3ccccc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from iodo-benzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.01 (s, 1H), 8.00 (d, 1H), 7.93 (d, 1H), 7.33-7.52 (m, 12H), 7.05 (dt, 1H), 6.66 (m, 2H), 6.43 (d, 2H), 4.96 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([Br:10])=[CH:4][N:3]=1.N([O-])=O.[Na+].[ClH:15]>O>[Br:10][C:5]1[CH:6]=[C:7]([C:8]#[N:9])[C:2]([Cl:15])=[N:3][CH:4]=1
Reactant: Cl
Reactant: N#Cc1cc(Br)cnc1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1cc(Br)cnc1Cl
Yield: 70 %

Procedure:
Compound 2 was dissolved in conc. HCl at 0° C., to which 1.1 equivalent of NaNO2 in H2O was added dropwise. Precipitation was formed. The white solid was filtered off, which gave the title compound 3. Overall yield was 70%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:29])[N:18]=[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:12]2[N:11]=1)[CH3:2].[S:30]([Cl:34])(=O)(=[O:32])[OH:31].S(Cl)(Cl)(=O)=O>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:30]([Cl:34])(=[O:32])=[O:31])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:29])[N:18]=[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:12]2[N:11]=1)[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCCCCCCc1nc(C)c2c(=O)[nH]c(-c3ccccc3OCC)nn12
Solvent: O=S(=O)(Cl)Cl
Product: CCCCCCCCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 400 mg (1 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-n-nonyl-3H-imidazo-[5,1-f][1,2,4]triazin-4-one (Example 24A) and 1.18 g (10 mmol) of chlorosulphuric acid. This gives 402 mg (80.1%) of sulphonyl chloride which is directly reacted further.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[F:11].[BH4-].[Na+].O>CO.Cl[Ni]Cl>[Br:1][C:2]1[C:3]([F:11])=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: O=[N+]([O-])c1cccc(F)c1Br
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1cccc(F)c1Br
Reaction time: 0.08 h
Yield: 63.2 %

Procedure:
To a solution of 2-bromo-1-fluoro-3-nitrobenzene (1.0 g, 5.0 mmol) in CH3OH (50 mL) was added NiCl2 (2.2 g 10 mmol) and NaBH4 (0.50 g 14 mmol) at 0° C. After the addition, the mixture was stirred for 5 min. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL×3). The organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 2-bromo-3-fluoroaniline (600 mg, 70%). 1H NMR (400 MHz, CDCl3) δ 7.07-7.02 (m, 1H), 6.55-6.49 (m, 1H), 4.22 (br s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH3:12][Si](C=[N+]=[N-])(C)C>O1CCCC1.CO>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1cc(Br)ccc1C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a cooled (0° C.) solution of 4-bromo-2-methylbenzoic acid (15.1 g, 0.070 mol) in tetrahydrofuran (180 mL) and methanol (45 mL) was slowly added (trimethylsilyl)diazomethane (2.0M in hexanes, 42 mL, 0.084 mol). The reaction mixture was allowed to warm to room temperature and stirred for 1 h, at which time it was concentrated in vacuo to afford methyl 4-bromo-2-methylbenzoate (16 g, 100%) as a yellow oil. The residue was taken to the next step without further purification. 1H NMR (400 MHz, CDCl3): 7.78 (d, 1H), 7.42 (s, 1H), 7.38 (d, 1H), 3.88 (s, 3H), 2.58 (s, 3H). MS (EI) for C9H9BrO2: 230 (MH+).