Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[N:31]=[C:30]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[CH:28][CH:29]=[C:30]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[N:31]=4)[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCC3)CC2)n1

Procedure:
Example 66 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz; CDCl3) δ 8.06 (d, 1H, J=8.4 Hz), 7.79 (s, 1H), 7.64 (t, 1H, J=7.6 Hz), 7.38–7.34 (m, 2H), 7.01–6.97 (m, 2H), 6.88 (d, 1H, J=7.2 Hz), 6.53 (br s, 1H), 3.27 (dd, 2H, J=6.0, 12.4 Hz), 2.94 (d, 2H, J=14.0 Hz), 2.54–2.48 (m, 4H), 2.32 (t, 2H, J=6.4 Hz), 1.99–1.60 (m, 14H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 495.3 (M+H)+.
Reaction SMILES: C([NH:8][C@H:9]([C:13](O)=[O:14])[CH:10]([CH3:12])[CH3:11])(OC(C)(C)C)=O.[ClH:16].[NH2:17][N:18]1[C:24](=[O:25])[CH:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[C:20]2[CH:36]=[CH:37][CH:38]=[CH:39][C:19]1=2>>[ClH:16].[NH2:8][C@H:9]([C:13]([NH:17][N:18]1[C:24](=[O:25])[CH:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[C:20]2[CH:36]=[CH:37][CH:38]=[CH:39][C:19]1=2)=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CCCCCCC1C(=O)N(N)c2ccccc2-c2ccccc21
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: CCCCCCC1C(=O)N(NC(=O)[C@@H](N)C(C)C)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using N-Boc-L-valine (Aldrich) and 5-amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 11), the title compound was prepared.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][CH2:9][C:10]([NH:12][CH2:13][CH:14]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)=O>O1CCCC1>[CH3:7][O:8][CH2:9][CH2:10][NH:12][CH2:13][CH:14]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1
Reactant: COCC(=O)NCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCNCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1

Procedure:
A suspension of 1.5 g of LiAlH4 in 30 ml of tetrahydrofuran (THF) is refluxed and a solution of 7.5 g of the product obtained in step 1 in 40 ml of THF are added dropwise thereto.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3[O:17][C:16]([P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][CH:14]=3)[N:9]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:8]=2[C:7]([CH:30]=[CH2:31])=[CH:6][C:5]=1[F:32])([O-:3])=[O:2].[N+](=[CH2:35])=[N-]>CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[N+:1]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3[O:17][C:16]([P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][CH:14]=3)[N:9]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:8]=2[C:7]([CH:30]2[CH2:35][CH2:31]2)=[CH:6][C:5]=1[F:32])([O-:3])=[O:2]
Reactant: C=Cc1cc(F)c([N+](=O)[O-])c2nc(-c3ccc(P(=O)(OCC)OCC)o3)n(CC(C)C)c12
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CCOP(=O)(OCC)c1ccc(-c2nc3c([N+](=O)[O-])c(F)cc(C4CC4)c3n2CC(C)C)o1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 1.0 mmol of 4-nitro-7-vinyl-5-fluoro-1-isobutyl-2-(2-diethylphosphono-5-furanyl)benzimidazole and 0.1 mmol of Pd(OAc)2 in 8 mL of ether was added an ether solution of diazomethane (generated from 3.0 g of 1-methyl-3-nitro-1-nitrosoguanidine) at 0 ° C. After stirring at room temperature 20 h solvent was removed and the residue chromatographed to give 4-nitro-7-cyclopropyl-5-fluoro-1-isobutyl-2-(2-diethylphosphono-5-furanyl)benzimidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][Br:18])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=2)=O)=[CH:4][CH:3]=1.CCN(CC)CC>ClCCCl>[Br:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[O:22][C:6]([C:5]3[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:8][N:9]=2)=[CH:12][C:13]=1[N+:19]([O-:21])=[O:20]
Reactant: O=C(NNC(=O)c1ccc(CBr)c([N+](=O)[O-])c1)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=[N+]([O-])c1cc(-c2nnc(-c3ccc(Cl)cc3)o2)ccc1CBr
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
To a 100 mL round-bottom flask was added 2.1 g (12.3 mmol) of 4-chlorobenzoic acid hydrazide, 3.20 g (12.3 mmol) of 4-bromomethyl-3-nitro benzoic acid, 3.54 g (18.5 mmol) of EDC, and 200 mL of DCM. Allowed to stir at room temperature for 18 h. Removed ⅔ of DCM, added water and filtered off white solid and washed with Et2O to give 3-nitro-4-bromomethyl-benzoic acid N′-(4-chloro-benzoyl)-hydrazide as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.99 (s, 1H) 5.12 (s, 1H) 7.59-7.64 (m, 2H) 7.91-7.95 (m, 2H) 7.96 (d, J=8.21 Hz, 1H) 8.22-8.29 (m, 1H) 8.57 (dd, J=6.57, 1.77 Hz, 1H) 10.76 (s, 1H) 10.94 (dd, J=5.18, 0.88 Hz, 1H). MS (m/z) 413.9 M (+1), tR=1.28, Meth 10. To a 500 mL round-bottom flask was added 4.95 g (12.0 mmol) of 3-nitro-4-bromomethyl-benzoic acid N′-(4-chloro-benzoyl)-hydrazide, 6.09 g (36.0 mmol) DMC, and 100 mL of DCE. To this pale yellow solution was added 6.70 mL (48.0 mmol) of Et3N, slowly over 5 min. The dark green solution was allowed to stir at 40° C. for 30 min. then cooled to room temperature stirred for 18 h. Removed solvent and purified over a silica plug 10-30% EtOAc/Hep to give the title compound as yellow solid. MS (m/z) 350.0 M (+1), retention time=1.51, Method 10.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=C(OC)C=CC=1C[N:26]([C:49]1[S:53][N:52]=[CH:51][N:50]=1)[S:27]([C:30]1[CH:38]=[C:37]2[C:33]([C:34](B3OC(C)(C)C(C)(C)O3)=[CH:35][N:36]2[CH3:39])=[CH:32][CH:31]=1)(=[O:29])=[O:28].C(O)(C(F)(F)F)=O>CN(C=O)C.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:34]2[C:33]3[C:37](=[CH:38][C:30]([S:27]([NH:26][C:49]4[S:53][N:52]=[CH:51][N:50]=4)(=[O:28])=[O:29])=[CH:31][CH:32]=3)[N:36]([CH3:39])[CH:35]=2)=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1
Reactant: FC(F)(F)c1cc(Br)ccc1I
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c3c2)c(OC)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc(Br)cc2C(F)(F)F)c2ccc(S(=O)(=O)Nc3ncns3)cc21
Temperature: 85 °C
Reaction time: 3 h

Procedure:
A vial containing 4-bromo-1-iodo-2-(trifluoromethyl)benzene was charged with potassium phosphate (0.130 g, 0.614 mmol), followed by a solution of N-(2,4-dimethoxybenzyl)-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (Intermediate H) (0.100 g, 0.175 mmol) and PdCl2(dppf)-CH2Cl2 (0.014 g, 0.018 mmol) in 1 mL of DMF. The vial was sealed and placed in a shaker block. The block was shaken for three hours at 85° C. The solution was filtered, washed with DMF and concentrated. The resulting solid was treated with a solution of TFA (0.270 mL, 3.51 mmol) in 1 mL of DCM. The vial was shaken at room temperature for two hours. The solution was concentrated and purified via reverse phase HPLC (8 min gradient elution 15 to 75% ACN/H2O, 0.1% TFA modifier) to afford 3-(4-bromo-2-(trifluoromethyl)phenyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ 3.95 (s, 3 H) 7.40-7.51 (m, 3 H) 7.69 (s, 1 H) 7.92-8.00 (m, 2 H) 8.03 (d, J=1.95 Hz, 1 H) 8.40 (s, 1 H). m/z (ESI) 515.9 (M+H)+.
Reaction SMILES: C1(S([N:10]2[C:14]3[C:15]4[C:20]([CH2:21][C:13]=3[C:12]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][S:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)(=[O:31])=[O:30])=[CH:24][CH:23]=3)=[N:11]2)=[CH:19][CH:18]=[CH:17][CH:16]=4)(=O)=O)C=CC=CC=1.[OH-].[Na+].Cl>CO>[NH:10]1[C:14]2[C:15]3[C:20]([CH2:21][C:13]=2[C:12]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][S:29]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)(=[O:30])=[O:31])=[CH:24][CH:23]=2)=[N:11]1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: O=S(=O)(Nc1ccc(-c2nn(S(=O)(=O)c3ccccc3)c3c2Cc2ccccc2-3)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=S(=O)(Nc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34 %

Procedure:
N-[4-(1-benzenesulphonyl-1,4-dihydroindeno[1,2-c]pyrazol-3-yl) phenyl]benzenesulphonamide (0.56 g) was suspended in methanol (40 ml) and a 2N aqueous solution of sodium hydroxide (5.3 ml) added at ambient temperature. A clear solution was obtained. The reaction mixture was stirred at ambient temperature for about 20 minutes and then poured onto a 2N aqueous solution of hydrochloric acid (75 ml). A colourless solid precipitated, which was collected by filtration (0.42 g). The solid was partitioned between an aqueous solution of sodium bicarbonate (25 ml) and ethyl acetate (25 ml), and stirred for about 30 minutes at ambient temperature. It was then collected by filtration and dried in vacuo at about 60° C. to give N-[4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenyl]benzenesulphonamide as a colourless solid (0.14 g) m.p. 286-288° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:13])[CH2:11][CH3:12])=[C:6]([OH:14])[CH:5]=1.Br[CH2:16][C:17]#[CH:18]>CN(C=O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:13])[CH2:11][CH3:12])=[C:6]([O:14][CH2:18][C:17]#[CH:16])[CH:5]=1
Reactant: C#CCBr
Reactant: CCC(=O)c1ccc(F)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(F)ccc1C(=O)CC
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
To a mixture of NaH (95%, 278 mg, 11 mmol) in DMF (20 mL) at 0° C., was added 1-(4-fluoro-2-hydroxy-phenyl)-propan-1-one (1.68 g, 10 mmol) in DMF (5 mL). After 15 min at 0° C., was 3-bromo-propyne (3.02 g, 20 mmol) added to the reaction mixture. After 1 h at 0° C., was the reaction mixture allowed to assume room temperature. The reaction mixture was extracted with H2O (100 mL). The H2O phase was washed with Et2O (3×100 mL) and the solvent of the combined organic phases was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, CH2Cl2), to give 1.40 g (68%) of 1-(4-fluoro-2-prop-2-ynyloxy-phenyl)-propan-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8].B#B>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([CH:16]=1)[CH:7]([OH:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15]
Reactant: O=C(c1cc(Cl)ccc1O)c1ccccc1F
Agent: B#B
Solvent: C1CCOC1
Product: Oc1ccc(Cl)cc1C(O)c1ccccc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under anhydrous conditions, a stirred solution of 25.0 g (99.5 mmoles) of 5-chloro-2'-fluoro-2-hydroxybenzophenone in 250 ml of anhydrous THF was heated to reflux. The heat source was removed and 115 ml (115 mmoles) of a solution (1M in BH3) of diborane in THF was added rapidly from a dropping funnel; foaming and some refluxing occurred. After addition, external heating was resumed and refluxing was continued for 5 min. A few minutes after heating was resumed, the yellow color of the ketone was discharged. The colorless solution was cooled to room temperature and worked up as described in Example 1a. An oil was obtained in quantitative yield which was used without further purification in the next step.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:24](=[O:26])[CH3:25])[CH:8]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][O:17]C2CCCCO2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[Br-:27].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>CO.C1COCC1.C(Cl)Cl>[Br:27][CH2:25][C:24]([C:7]1[CH:8]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][OH:17])[C:10]([O:11][CH3:12])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)=[O:26]
Reactant: [Br-]
Reactant: COc1c(OCCCOC2CCCCO2)cc(C(C)=O)cc1C(C)(C)C
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COc1c(OCCCO)cc(C(=O)CBr)cc1C(C)(C)C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
1-{3-tert-Butyl-4-methoxy-5-[3-(tetrahydropyran-2-yloxy)propoxy]phenyl}ethanone (O2.071; 12.7 g) was dissolved in methanol/THF (200/200 ml) and admixed with phenyltrimethylammonium tribromide (13.1 g) while stirring. The mixture was stirred at RT for 1 h, then diluted with DCM and washed once with 5% sodium thiosulfate solution. The DCM phase was dried over magnesium sulfate, filtered and concentrated. The residue was taken up in acetonitrile (100 ml) and admixed with 48% hydrobromic acid (5.91 ml). The mixture was left to stand for 1 h, then admixed with water, extracted by shaking with EA, and the combined EA phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel (120 g cartridge, n-heptane/MtB ether gradient of 0-100% in 60 min). 3.29 g of the title compound were obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:6]2[C:5]=1[NH:19][C@H:20]1[CH2:24][CH2:23][C@@:22]([CH2:26][NH:27]C(=O)OC(C)(C)C)([CH3:25])[C:21]1([CH3:36])[CH3:35])(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[NH2:27][CH2:26][C@@:22]1([CH3:25])[CH2:23][CH2:24][C@H:20]([NH:19][C:5]2[C:6]3[N:7]([CH:10]=[C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:12]=3)[N:8]=[CH:9][C:4]=2[C:1]([NH2:2])=[O:3])[C:21]1([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NC[C@@]1(C)CC[C@H](Nc2c(C(N)=O)cnn3cc(-c4ccccc4)cc23)C1(C)C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)[C@@H](Nc2c(C(N)=O)cnn3cc(-c4ccccc4)cc23)CC[C@]1(C)CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a solution of tert-butyl (((1S,3S)-3-((3-carbamoyl-6-phenylpyrrolo[1,2-b]pyridazin-4-yl)amino)-1,2,2-trimethylcyclopentyl)methyl)carbamate (236 mg, 0.480 mmol) in dichloromethane (3910 μl) at 0° C. was added trifluoroacetic acid (452 μl, 5.87 mmol. The reaction mixture was allowed to warm to room temperature and stirring was continued for 1 hr. The reaction mixture was concentrated under reduced pressure, yielding a yellow oil. The oil was diluted with ethyl acetate (50 ml) and washed successively with saturated sodium bicarbonate, water, and saturated sodium chloride. The ethyl acetate extract was dried with sodium sulfate, filtered, and concentrated under reduce pressure, yielding 4-(((1S,3S)-3-(aminomethyl)-2,2,3-trimethylcyclopentyl)amino)-6-phenylpyrrolo[1,2-b]pyridazine-3-carboxamide (182 mg, 0.465 mmol, 97% yield) as a tan solid. ESI-MS m/z 392.3 ([M+H]+).
Reaction SMILES: [CH2:1]([N+:5]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[NH2:18][C:19]1([O:28][CH3:29])[CH2:22][N:21]([S:23]([O-:26])(=[O:25])=[O:24])[C:20]1=[O:27].N1C=CC=CC=1.[CH2:36]([O:43][C:44]([CH:46]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:47](Cl)=[O:48])=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.C(Cl)Cl>[CH2:14]([N+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16][CH3:17].[O:48]=[C:47]([NH:18][C:19]1([O:28][CH3:29])[CH2:22][N:21]([S:23]([O-:26])(=[O:24])=[O:25])[C:20]1=[O:27])[CH:46]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:44](=[O:45])[O:43][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)C(C(=O)OCc1ccccc1)c1ccccc1
Reactant: COC1(N)CN(S(=O)(=O)[O-])C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC#N
Product: COC1(NC(=O)C(C(=O)OCc2ccccc2)c2ccccc2)CN(S(=O)(=O)[O-])C1=O
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 69.2 %

Procedure:
Crude 3-amino-3-methoxy-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt (431 mg, see Example 74), containing borax, is dissolved in 30 ml of dry acetonitrile. Dry pyridine (317 μl) is added and the solution stirred well at -10° C. under dry nitrogen. α-(Benzyloxycarbonyl)phenylacetyl chloride (568 mg) in 3 ml of dry acetonitrile is added dropwise. Thin layer chromatography indicates the reaction to be complete after 15 minutes. Potassium phosphate buffer (0.5M, pH 5.5, 17 ml) is added and most of the acetonitrile is removed in vacuo. The residue is diluted with water and extracted three times with equal volumes of methylene chloride. The extract is dried over anhydrous sodium sulfate and evaporated in vacuo to give 1.032 g of crude product, which is dissolved in 3 ml of methylene chloride and chromatographed on a silica column using methylene chloride-methanol to give 470 mg of the title compound.
Reaction SMILES: C[Si](C)(C)C1C=C(C=CC=1)N.Cl[C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=1.[CH3:23][C@@H:24]1[CH2:29][NH:28][CH2:27][CH2:26][NH:25]1>>[CH3:23][CH:24]1[NH:25][CH2:26][CH2:27][N:28]([C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:29]1
Reactant: C[C@@H]1CNCCN1
Reactant: FC(F)(F)c1cccnc1Cl
Agent: C[Si](C)(C)c1cccc(N)c1
Product: CC1CN(c2ncccc2C(F)(F)F)CCN1
Yield: 92.6 %

Procedure:
More specifically, compound 1 is 2-chloro-3-trifluoromethylpyridine (2 g); compound 2 is (R)-2-methyl piperazine; the synthesized compound 3 is 3-methyl-1-(3-trifluoromethyl-2-pyridyl)piperazine (2.5 g, yield about 92.6%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.Cl[C:31]([O:33][CH3:34])=[O:32]>C(Cl)Cl>[F:20][C:2]([F:19])([F:1])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][N:10]2[C:31]([O:33][CH3:34])=[O:32])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C1CCNC(c2cccc(C(F)(F)F)c2)C1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.1 %

Procedure:
Methyl 2-(3-(trifluoromethyl)phenyl)piperidine-4-carboxylate (1.4 g, 4.87 mmol) was dissolved in DCM (50 mL), then DIPEA (2.128 mL, 12.18 mmol) was added. Methyl chloroformate (0.537 mL, 6.82 mmol) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 4 h, washed with 0.1 M HCl (100 mL) and satd NaHCO3 (100 mL), dried through a phase separator and evaporated yielding dimethyl 2-(3-(trifluoromethyl)phenyl)piperidine-1,4-dicarboxylate (1.7 g, quant.) as an orange oil. MS m/z 346 (M+H)+
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[Si:12]([O:29][CH2:30][C:31]1[C:32]([N:47]2[CH2:52][C@H:51]([CH3:53])[O:50][C@H:49]([CH3:54])[CH2:48]2)=[C:33]([F:46])[C:34]([F:45])=[C:35]([CH:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[OH:38])[CH:36]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Si:12]([O:29][CH2:30][C:31]1[C:32]([N:47]2[CH2:48][C@H:49]([CH3:54])[O:50][C@H:51]([CH3:53])[CH2:52]2)=[C:33]([F:46])[C:34]([F:45])=[C:35]([C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)=[O:38])[CH:36]=1)([C:25]([CH3:26])([CH3:27])[CH3:28])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)c3ccccn3)c(F)c2F)C[C@H](C)O1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3ccccn3)c(F)c2F)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
PCC (1.07 g, 0.005 mmol) was added to a solution of {5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2,3-difluorophenyl}(pyridin-2-yl)methanol (Intermediate 18, 1.8 g, 0.002 mmol) in anhydrous DMC (15 mL) at 0° C. and the mixture was allowed to stir for 1 h at room temperature. The reaction mixture was filtered and the solvents were removed under vacuum and the residue was purified over silica gel chromatography column using an ethyl acetate-pet. ether gradient, providing the title compound. Yield: 1.5 g (83%). MS (ES) MH+: 603.2 for C35H40F2N2O3Si
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Product: O=[N+]([O-])c1ccc(-n2ccc3ccc(Cl)cc32)cc1

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-iodo-4-nitrobenzene: ESMS m/e: 272.6 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][C:9]1[N:10]=[N:11][C:12]([O:18][CH2:19][CH3:20])=[CH:13][C:14]=1[O:15][CH2:16][CH3:17].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)[N:23]=1>CN(C=O)C>[CH2:16]([O:15][C:14]1[CH:13]=[C:12]([O:18][CH2:19][CH3:20])[N:11]=[N:10][C:9]=1[CH2:8][N:32]1[CH:31]=[CH:30][N:29]=[C:28]1[C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([F:21])[N:23]=1)[CH3:17]
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Reactant: CCOc1cc(OCC)c(CCl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(OCC)c(Cn2ccnc2-c2cccc(F)n2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Excess K2CO3 is added to a stirred solution of 3-chloromethyl-4,6-diethoxy-pyridazine (70 mg, 0.32 mmol) and 2-fluoro-6-(1H-imidazol-2-yl)-pyridine (52 mg, 0.32 mmol) in DMF (6 mL). The mixture is stirred at room temperature overnight. The solvent is removed in vacuo and water (5 mL) and EtOAc (8 mL) are added. The layers are separated and the aqueous layer is extracted with EtOAc (8 mL). The combined extracts is washed with brine (10 mL) and dried (Na2SO4) and evaporated. Preparative TLC purification of the residue (5% MeOH in CH2Cl2) provides the title compound as a light yellow oil. H1 NMR δ (CDCl3) 8.07–8.10 (m, 1H), 7.82 (q, 1H, J=7.8 Hz), 7.14 (s, 2H), 6.80–6.84 (m, 1H), 6.22 (s, 1H), 6.11 (s, 2H), 4.50 (q, 2H, J=7.2 Hz), 3.95 (q, 2H, J=7.2 Hz), 1.39 (t, 3H, J=7.2 Hz), 1.18 (t, 3H, J=7.2 Hz).
Reaction SMILES: [O:1]=[C:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[C:2]([CH:3]([C:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[CH2:16])[C:4]([O:6][CH3:7])=[O:5])(=[O:1])[CH3:8]
Reactant: C#Cc1ccccc1
Reactant: COC(=O)CC(C)=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=C(c1ccccc1)C(C(C)=O)C(=O)OC
Temperature: 50 °C
Reaction time: 18 h
Yield: 83.3 %

Procedure:
A suspension of 3.2 g (27.5 mmol) of methyl 3-oxobutanoate, 5.6 g (55.0 mmol) of phenylacetylene and 700 mg (0.8 mmol) of *[ReBr(CO)3(THF)]2 in 55 mL of anhydrous toluene is stirred for 18 hours at 50° C. After cooling to room temperature, the medium is concentrated under reduced pressure. The residue obtained is taken up in 100 mL of DCM, washed successively with water (100 mL) and brine (100 mL), dried over Na2SO4 and then concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a 99/1 DCM/MeOH mixture. 5 g of methyl 2-acetyl-3-phenylbut-3-enoate are obtained in the form of a yellow oil.