Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5](=[C:9]1[NH:14][CH2:13][CH2:12][CH2:11][S:10]1)[N+:6]([O-:8])=[O:7])[CH3:2].CC(C)=[O:17].I([O-])(=O)(=O)=O.[Na+].C(Cl)Cl>O>[CH2:1]([S:3]([CH2:4][C:5](=[C:9]1[NH:14][CH2:13][CH2:12][CH2:11][S:10]1)[N+:6]([O-:8])=[O:7])=[O:17])[CH3:2]
Reactant: CC(C)=O
Reactant: CCSCC(=C1NCCCS1)[N+](=O)[O-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: CCS(=O)CC(=C1NCCCS1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2.34 g of 25 and 10 ml of acetone was added all at once to a solution of 2.25 g of sodium periodate in 15 ml of water. The resulting exothermic reaction was controlled between 25° and 35° by cooling. The mixture then as stirred at room temperature for 90 minutes, then was poured into a mixture of water and methylene chloride. The separated organic phase was washed with saturated sodium thiosulfate solution, and saturated sodium chloride. It then was dried (MgSO4) and the solvent evaporated under reduced pressure to give an oil, which was triturated with ether to give a yellow solid. This was chromatographed by a preparative thin layer chromatographic technique, on silica gel and using a mixture of methanol (2%) in methylene chloride as eluent, to give 26, as a yellow solid, m.p.: 102°-104°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.[C:43]([NH:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[NH2:57])([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>CN(C=O)C>[C:46]([O:45][C:43]([NH:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[NH:57][C:17]([C:15]1[NH:14][C:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C:10]=2[CH:16]=1)=[O:19])=[O:44])([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c(C(=O)O)cc2C1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2c([nH]1)CCN(C(=O)OC(C)(C)C)C2
Reaction time: 1 h

Procedure:
To a solution of compound 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (1.0 eq) in DMF was added triethyl amine (2.2 eq), Bis (2-oxo-3-oxazolidinyl) phosphonic chloride (BOP, 1.2 eq.) and stirred for 1 hr. Monoboc phenylene diamine was added and reaction was stirred for 24 hrs. Reaction mixture was then quenched with water and extracted with ethyl acetate, dried over sodium sulphate and concentrated to dryness. Crude mass was then purified by silica gel column chromatography to afford tert-butyl 2-({2-[(tert-butoxycarbonyl)amino]phenyl}carbamoyl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, which was then reacted with hydrochloric acid saturated diethyl ether to get N-(2-aminophenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2]pyridine-2-carboxamide
Reaction SMILES: [F:1][CH2:2][C@H:3]1[CH2:8][NH:7][CH2:6][C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4]1.Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25]>>[F:1][CH2:2][C@H:3]1[CH2:8][N:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[CH2:6][C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](CF)C1
Reactant: O=[N+]([O-])c1cnccc1Cl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CF)CN(c2ccncc2[N+](=O)[O-])C1

Procedure:
Method 1 of example 1 was followed using cis(+/−)-tert-butyl 5-(fluoromethyl)piperidin-3-ylcarbamate and 4-chloro-3-nitropyridine yielding cis(+/−)-tert-butyl 5-(fluoromethyl)-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate. LCMS (m/z): 355.1 (MH+); LC Rt=2.41 min.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)OCC[O:20]2)=[CH:15][CH:14]=1.C(N(CC)CC)C>C(O)(C)C>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[N:11][C:2]=1[N:30]1[CH2:29][CH2:28][N:27]([CH2:26][CH2:25][CH2:24][C:19]([C:16]2[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=2)=[O:20])[CH2:32][CH2:31]1
Reactant: Clc1ncc2ccccc2n1
Reactant: Fc1ccc(C2(CCCN3CCNCC3)OCCO2)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C(CCCN1CCN(c2ncc3ccccc3n2)CC1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2.25 g 2-Chloroquinazoline, 4.2 g 1-(3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-propyl)piperazine and 2 ml triethylamine in 8 ml isopropanol are stirred and heated 21/2 hours at 80° C. The solvent is then evaporated in vacuo and the residue is taken up in hexane. The hexane solution is treated with charcoal, filtered and concentrated whereby the ketal of the title compound crystallizes out. The resulting precipitate is dissolved in 40 ml aqueous 1N hydrochloric acid. After 1 hour the acidic solution is made alkaline with aqueous ammonia. The resulting precipitate is filtered off and recrystallized from ethyl acetate to give the title compound, m.p. 129°-131° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]1[O:5][CH2:4]1.[Cl-].[NH4+].[N-:10]=[N+:11]=[N-:12].[Na+]>C(O)C>[N:10]([CH2:4][CH:3]([OH:5])[C:2]([F:7])([F:6])[F:1])=[N+:11]=[N-:12]
Reactant: FC(F)(F)C1CO1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCC(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 1,1,1-trifluoro-2,3-epoxypropane (2.0 g, 18 mmol) in 70% ethanol (20 mL) was added ammonium chloride (1.9 g, 36 mmol) followed by sodium azide (2.3 g, 36 mmol). The reaction mixture was stirred at room temperature. After 6 h, the reaction mixture was partitioned between water (100 mL) and diethyl ether (100 mL). The organic layer was washed with additional water (100 mL). The first aqueous layer was back-extracted with diethyl ether (100 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give 3-azido-1,1,1-trifluoropropan-2-ol as a crude oil. 1H NMR (600 MHz, DMSO-D6) 4.14 (m, 1H); 3.58-3.49 (m, 2H); 2.58 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.[BH3-]C#[N:14].[Na+]>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH2:14]
Reactant: O=C1CCc2c(Br)cccc21
Reactant: [BH3-]C#N
Agent: [Na+]
Product: NC1CCc2c(Br)cccc21

Procedure:
The title amine was generated from 4-bromo-indan-1-one (5.00 g, 23.70 mmol), NaBH3CN (10.40 g, 165.50 mmol) and NH4OAc (54.80 g, 710.95 mmol) according to the protocols as outlined in general procedure B described above.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[C:5]([CH3:8])=[N:6][CH:7]=1.C([O-])(=O)C.[K+].CC([N+:22]([O-])=O)(C)C.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]([C:10](=[O:12])[CH3:11])[N:22]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)[N+](=O)[O-]
Reactant: CC(=O)Nc1cc(Br)cnc1C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)n1ncc2ncc(Br)cc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
A solution of N-(5-bromo-2-methylpyridin-3-yl)acetamide (2.8 g, 12 mmol) and potassium acetate (3.59 g, 36.6 mmol) in toluene (50 mL) was heated at 80° C. under nitrogen. After 30 min, 2-methyl-2-nitropropane (3.77 g, 36.6 mmol) and acetic anhydride (3.73 g, 36.6 mmol) were added, and the resulting mixture was stirred at 80° C. for another 18 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with water (50 mL). The aqueous mixture was extracted with ethyl acetate (3×60 mL). The collected organic extractions were concentrated in vacuo. Purification by flash column chromatography (5→10% ethyl acetate in petroleum ether) afforded 1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethanone (1.4 g, 48.% yield). 1H NMR (400 MHz, Chloroform-d) δ 8.90 (s, 1 H), 8.75 (s, 1 H), 8.32 (s, 1 H), 2.79 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH:17]=O)[CH2:13][CH2:12]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:22][C:23](=[O:44])[CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:21]>ClCCl>[CH2:20]([O:22][C:23](=[O:44])/[CH:24]=[CH:17]/[C@H:14]1[CH2:15][CH2:16][C@H:11]([CH2:10][CH2:9][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:19])[CH3:8])[CH2:12][CH2:13]1)[CH3:21]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(CC[C@H]1CC[C@H](C=O)CC1)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CCOC(=O)/C=C/[C@H]1CC[C@H](CCN(C)C(=O)OC(C)(C)C)CC1
Yield: 75.5 %

Procedure:
A solution of 4.02 g (14.9 mmol) trans-[2-(4-formyl-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester and 5.47 g (14.9 mmol) of (triphenyl-phosphoranylidene)-acetic acid ethyl ester in 40 ml of dichloromethane was stirred at room temperature for 60 hours. After concentration under reduced pressure, the crude product was chromatographed on silica gel with a 9:1 v/v mixture of hexane and ethylacetate as the eluent giving 3.82 g (75.4%) of pure trans-3-{4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexyl}-(E)-acrylic acid ethyl ester as colorless viscous oil, MS: 340 (MH+).
Reaction SMILES: BrN1C(=O)CCC1=O.Br[CH2:10][Br:11].[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1C>C(Cl)(Cl)Cl>[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:10][Br:11]
Reactant: COC(=O)c1ccccc1C
Reactant: BrCBr
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccccc1CBr
Yield: 76.3 %

Procedure:
A solution of N-bromosuccinimide, dibromomethane (3.56 g, 20 mmol) and methyl-2-methylbenzoate (3.04 g, 20 mmol) in 30 mL CHCl3 was refluxed for 4 h. The solvent was evaporated and the residue was purified by column chromatography, with EtOAc:hexanes, 1:5, as eluant, yielding (3.496 g, 76%) of 2-bromomethyl-benzoic acid methyl ester. A solution of 2-bromomethyl-benzoic acid methyl ester (368 mg, 2 mmol) and morpholine (174 mg, 2.0 mmol) in 8 mL DMF with 1 mL HCl (2 N) was refluxed overnight. The solvent was evaporated in vacuo and the residue was purified by column chromatography with EtOAc:hexanes, 1:4, yielding (180 mg, 38%) 2-(morpholin-4-ylmethyl)-benzoic acid methyl ester. The title compound was prepared from 2-(morpholin-4-ylmethyl)-benzoic acid methyl ester, hydrazine and then 3-trifluoromethyl-benzaldehyde in two steps by procedures similar to Example 29. 1H NMR (CDCl3): 8.46 (s, 1H), 8.02 (m, 2H), 7.96 (d, J=7.8 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.45 (m, 2H), 7.22 (m, 1H), 3.82 (t, J=4.8 Hz, 4H), 2.64 (t, J=4.8 Hz, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11]Br)=[CH:8][C:9]=1[Br:10])=[O:4].C([O-])(O)=[O:14].[Na+].CCOC(C)=O>CS(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][OH:14])=[CH:8][C:9]=1[Br:10])=[O:4]
Reactant: COC(=O)c1sc(CBr)cc1Br
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(CO)cc1Br
Temperature: 115 °C
Yield: 24 %

Procedure:
A mixture of 3-Bromo-5-bromomethyl-thiophene-2-carboxylic acid methyl ester (0.99 g, 3.15 mmol) and NaHCO3 (4.5 g, 53.6 mmol) in DMSO (25 ml) was heated at 115° C. for 3 h. The reaction mixture was cooled. The reaction mixture was EtOAc (250 ml), washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column (0-30% EtOAc in hexane) to give 0.19 g (24%) yellow solid product.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@@H:8]([CH2:12][S:13][S:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:9]([OH:11])=O)=[O:6])[CH:2]=[CH2:3].ON1C(=O)CCC1=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[NH:48]([C:58]([O:60][CH2:61][CH:62]1[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[C:68]2[C:63]1=[CH:64][CH:65]=[CH:66][CH:67]=2)=[O:59])[C@H:49]([C:55]([OH:57])=[O:56])[CH2:50][CH2:51][CH2:52][CH2:53][NH2:54].Cl>ClCCl>[CH:64]1[C:63]2[CH:62]([CH2:61][O:60][C:58]([NH:48][C@@H:49]([CH2:50][CH2:51][CH2:52][CH2:53][NH:54][C:9](=[O:11])[C@@H:8]([NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH2:12][S:13][S:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:55]([OH:57])=[O:56])=[O:59])[C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[C:68]=2[CH:67]=[CH:66][CH:65]=1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: C=CCOC(=O)N[C@@H](CSSC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N[C@@H](CSSC(C)(C)C)C(=O)NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.8 %

Procedure:
A solution of (R)-2-(allyloxycarbonylamino)-3-(tert-butyldisulfanyl)propanoic acid (Alloc-Cys(StBu)-OH) (1.9 g, 6.48 mmol) and N-hydroxysuccinimide (0.745 g, 6.48 mmol) in dichloromethane (10 ml) was cooled to 0° C., after which 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl, 1.24 g, 6.48 mmol) was added and the reaction solution was stirred at room temperature for 20 hours. After 20 hours, the reaction solution was cooled to 0° C., after which N,N-diisopropylethylamine (2.49 ml, 14.25 mmol) and Fmoc-Lys-OH (2.39 g, 6.48 mmol) were added and the reaction solution was stirred at room temperature for 2 hours. Dichloromethane and 1 M hydrochloric acid were added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with 25 wt % brine, the resulting solution was concentrated under reduced pressure, and the concentration residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6-((R)-2-(allyloxycarbonylamino)-3-(tert-butyldisulfanyl)propanamido)hexanoic acid (Compound 150a, Fmoc-Lys(Alloc-Cys(StBu))-OH) (2.66 g, 64%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[CH3:17][NH:18][C:19]([C:21]1[C:29]2[C:24](=[CH:25][C:26]([OH:30])=[CH:27][CH:28]=2)[N:23]([CH3:31])[C:22]=1[CH2:32][CH3:33])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:17][NH:18][C:19]([C:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=5)[S:10][C:3]=34)=[CH:27][CH:28]=2)[N:23]([CH3:31])[C:22]=1[CH2:32][CH3:33])=[O:20]
Reactant: CCc1c(C(=O)NC)c2ccc(O)cc2n1C
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1c(C(=O)NC)c2ccc(Oc3ccnc4cc(-c5nccn5C)sc34)cc2n1C
Yield: 39.4 %

Procedure:
This material was prepared by the reaction 7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e (0.084 g, 0.34 mmole) with 2-ethyl-6-hydroxy-N,1-dimethyl-1H-indole-3-carboxamide 73g (0.078 g, 0.33 mmole) and Cs2CO3 (0.111 g, 0.34 mmole) in a manner as previously described for example 1 to give an off-white solid (0.058 g, 40%). 1H NMR (300 MHz, CD3OD δ 8.27 (1H, d, J=5.4 Hz), 7.68 (1H, d, J=8.6 Hz), 7.59 (1H, s), 7.24 (1H, d, J=1.9 Hz), 7.17 (1H, s), 6.96 (1H, s), 6.90 (1H, dd, J=1.9, 8.6 Hz), 6.50 (1H, d, J=5.4 Hz), 3.87 (3H, s), 3.58 (3H, s), 3.01 (2H, m), 2.85 (3H, s), 1.14 (3H, m). HRMS (MH+): Calcd: 446.1655. Found: 446.1651.
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[CH2:8]([O:10][C:11](=[O:22])[C:12]([C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1[F:21])=O)[CH3:9]>O1CCCC1.C(OCC)(=O)C.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH2:8]([O:10][C:11](=[O:22])/[C:12](/[C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1[F:21])=[N:7]\[S@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH3:9]
Reactant: CCOC(=O)C(=O)c1cc(Br)ccc1F
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)/C(=N\[S@@](=O)C(C)(C)C)c1cc(Br)ccc1F
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
A solution of (S)-(−)-2-methyl-2-propanesulfinamide (2.35 g, 19.4 mmol) and (5-bromo-2-fluoro-phenyl)-oxo-acetic acid ethyl ester (5.33 g, 19.4 mmol) in tetrahydrofuran (80 ml) was treated at room temperature with titanium(IV) ethoxide (8.04 ml, 38.8 mmol). The light brown solution was stirred at 70° C. for 3.5 hours. For the workup, the cooled reaction mixture was poured into ice water, diluted with ethyl acetate, and filtered through a pad of Dicalite. The organic layer was separated, washed with brine, dried over sodium sulfate, and finally evaporated at reduced pressure. The crude product (6.7 g) was purified by chromatography on silica gel using a gradient of cyclohexane and dichloromethane=100/0 to 0/100 as the eluent. (S)-(5-bromo-2-fluoro-phenyl)-[(Z)-2-methyl-propane-2-sulfinylimino]-acetic acid ethyl ester was obtained as a yellow oil (4.9 g, 66% of theory). Mass (calculated) C14H17BrFNO3S [378.260]; (found) [M+H]+=378, [M+2-H]+=380.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([SiH2][O:24][C:25](C)(C)[C:26]1[CH:27]=[C:28]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH2:29][NH:30][C:31](=[O:37])[CH2:32][C:33]([F:36])([F:35])[F:34])(C)(C)C.CCOC(C)=O>C1COCC1>[Cl:41][C:40]1[CH:39]=[CH:38][C:28]([CH2:29][NH:30][C:31](=[O:37])[CH2:32][C:33]([F:36])([F:35])[F:34])=[CH:27][C:26]=1[CH2:25][OH:24]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CNC(=O)CC(F)(F)F)ccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CC(F)(F)F)NCc1ccc(Cl)c(CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
TBAF (1M in THF, 9.10 mL, 9.10 mmol) was added to a sol. of N-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzyl]-3,3,3-trifluoro-propionamide (1.80 g, 4.55 mmol) in THF (45 mL) at 0° C. The mixture was stirred for 1 h while warming up to rt. EtOAc (100 mL) was added, and the mixture was washed with aq. sat. NH4Cl (3×) and water (4×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 70:30) yielded the title compound (835 mg, 65%). LC-MS: tR=0.76 min; ES+: 323.02.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:13]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][CH:23]([NH:1][C:2]2[CH:12]=[CH:11][C:5]([C:6](=[O:7])[N:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CN(C)C(=O)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CN(C)C(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 100 %

Procedure:
Using general procedure A, 4-amino-N,N-dimethyl-benzamide (Schiemenz, G. P.; Stein, G., Tetrahedron, 26, 1970, 2007-2026) (619 mg, 3.77 mmol) and 1-Boc-4-piperidone (901 mg, 4.52 mmol) gave 4-(4-dimethylcarbamoyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (1.31 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13])[CH3:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:20][C:21]#[N:22]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19](/[C:20](=[CH:8]/[C:7]2[CH:10]=[CH:11][C:4]([O:3][CH2:1][CH3:2])=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=2)/[C:21]#[N:22])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: CCOc1ccc(C=O)cc1[N+](=O)[O-]
Product: CCOc1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1[N+](=O)[O-]
Yield: 39.9 %

Procedure:
4-Ethoxy-3-nitrobenzaldehyde (586 mg) and 3,4-dimethoxybenzyl cyanide (532 mg) were subjected to condensation in accordance with process B of (production process 2), to thereby produce the target product (425 mg, yield: 40%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][CH:8]([CH:13]1[C:26]3[CH:25]=[CH:24][C:23]([C:27]#[N:28])=[CH:22][C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[O:4].[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+].O>CN(C=O)C>[F:30][C:2]([F:29])([F:1])[C:3]([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][CH:8]([CH:13]1[C:26]3[CH:25]=[CH:24][C:23]([C:27]4[NH:33][N:32]=[N:31][N:28]=4)=[CH:22][C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[O:4]
Reactant: N#Cc1ccc2c(c1)Oc1ccccc1C2C1CC2CCC(C1)N2C(=O)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(N1C2CCC1CC(C1c3ccccc3Oc3cc(-c4nnn[nH]4)ccc31)C2)C(F)(F)F
Temperature: 120 °C
Yield: 86 %

Procedure:
To a solution of 9-[8-(2,2,2-trifluoroacetyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-9H-xanthene-3-carbonitrile, 3j (0.35 g; 0.848 mmol) in DMF (10 mL) were added sodium azide (0.165 g, 2.54 mmol) and ammonium chloride (0.136 g; 2.5 mmol), and the mixture was heated at 120° C. for 3 h. The mixture was allowed to cool to rt, poured into water, and the solid was separated via filtration, yielding 0.33 g (86%) of title compound 2,2,2-trifluoro-1-{3-[3-(1H-tetrazol-5-yl)-9H-xanthen-9-yl]-8-aza-bicyclo[3.2.1]oct-8-yl}-ethanone, 4j
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[CH2:35]([N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH:36]=[CH:37][CH3:38]>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:51]2[CH2:52][CH2:53][CH2:54][N:48]([C:40]3[N:39]([CH2:35][CH:36]=[CH:37][CH3:38])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:49][CH2:50]2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)=[O:6]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: CC=CCn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Product: CC=CCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 47.3 using 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (0.74 g, 1.41 mmol) and 4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.66 g, 1.40 mmol) to give the title compound: Rf=0.37 (silica gel, dichloromethane/methanol/concentrated aqueous ammonia 95/5/0.1).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1.[N+:14]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21])([O-:16])=[O:15]>ClCCl>[OH:13][CH:10]1[CH2:11][CH2:12][N:8]([C:20]([C:19]2[CH:23]=[CH:24][CH:25]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=2)=[O:21])[CH2:9]1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: OC1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCC(O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
2.22 g of triethylamine (20 mmol), followed by 1.74 g of pyrrolidin-3-ol (20 mmol), were added to a solution of 3.71 g of 3-nitrobenzoyl chloride (20 mmol) in 40 ml of dichloromethane cooled to 0° C. The reaction medium was stirred at ambient temperature for 2 hours and was then diluted with 50 ml of dichloromethane. The organic phase was washed with 50 ml of a 1 N hydrochloric acid solution and then with 50 ml of a saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated. 3.78 g of (3-hydroxypyrrolidin-1-yl)-(3-nitrophenyl)methanone were obtained and used without purification in the next step. Yield=80%.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[OH:10].C(N(CC)C(C)C)(C)C.Cl[CH2:21][O:22][CH3:23].Cl>ClCCl>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH2:21][O:22][CH3:23]
Reactant: O=Cc1ccc(F)c(O)c1
Reactant: COCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(C=O)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Fluoro-3-hydroxybenzaldehyde (11.9 g) and N,N-diisopropylethylamine (44 mL) were dissolved in dichloromethane (100 mL). To the mixture was added chloromethylmethylether (13 mL), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added dropwise 1 mol/L hydrochloric acid (250 mL), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (14.5 g).