Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:16](N(CC)C(C)C)(C)[CH3:17].C(I)C>CN(C=O)C>[CH2:16]([N:13]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:8][C:7]1[CH:14]=[CH:15][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:17]
Reactant: O=[N+]([O-])c1ccc(Cc2ncc[nH]2)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCI
Solvent: CN(C)C=O
Product: CCn1ccnc1Cc1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Yield: 20.5 %

Procedure:
To a solution of 2-(4-nitro-benzyl)-1H-imidazole (1.58 g, 7.37 mmol) in DMF (10 mL) was added N,N-diisopropylethyl amine (1.93 mL, 11.05 mmol) and heated to 5° C. for 30 min. Ethyl iodide (1.18 mL, 7.37 mmol) was added dropwise and the reaction mixture heated to reflux for 6 h. The solvent was evaporated under reduced pressure, the residue dissolved in dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered, evaporated and the residue purified by column chromatography over silica gel (60-120 mesh) using 3% methanol/chloroform as eluent to afford 1-ethyl-2-(4-nitrobenzyl)-1H-imidazole (0.35 g, 21%).
Reaction SMILES: C1C2C(=CC=C(NC3N=C(C4C(C5C=C(NC(=O)C6C=CC=CC=6)C=CC=5)=NN5C=CC=CC=45)C=CN=3)C=2)CCN1.Cl[C:43]1[N:48]=[C:47]([C:49]2[C:50]([C:58]3[CH:59]=[C:60]([NH:64][C:65](=[O:74])[C:66]4[C:71]([F:72])=[CH:70][CH:69]=[CH:68][C:67]=4[F:73])[CH:61]=[CH:62][CH:63]=3)=[N:51][N:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=23)[CH:46]=[CH:45][N:44]=1.[CH3:75][S:76]([CH:79]([C:81]1[CH:82]=[C:83]([NH2:87])[CH:84]=[CH:85][CH:86]=1)[CH3:80])(=[O:78])=[O:77]>>[F:73][C:67]1[CH:68]=[CH:69][CH:70]=[C:71]([F:72])[C:66]=1[C:65]([NH:64][C:60]1[CH:61]=[CH:62][CH:63]=[C:58]([C:50]2[C:49]([C:47]3[CH:46]=[CH:45][N:44]=[C:43]([NH:87][C:83]4[CH:84]=[CH:85][CH:86]=[C:81]([CH:79]([S:76]([CH3:75])(=[O:78])=[O:77])[CH3:80])[CH:82]=4)[N:48]=3)=[C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][N:52]3[N:51]=2)[CH:59]=1)=[O:74]
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: CC(c1cccc(N)c1)S(C)(=O)=O
Agent: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1
Product: CC(c1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)c1)S(C)(=O)=O

Procedure:
The title compound is racemic and may be prepared by a procedure similar to Example 27, Step D using N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and racemic {3-[1-(methylsulfonyl)ethyl]-phenyl}amine. 1H NMR (400 MHz, DMSO-d6): δ 10.92 (s, 1H); 9.63 (s, 1H); 8.82 (d, 1H); 8.50 (d, 1H); 8.24 (d, 1H); 7.98 (s, 1H); 7.82 (d, 1H); 7.76 (br s, 2H); 7.56 (qt, 1H); 7.47 (t, 2H); 7.35 (d, 1H); 7.23 (m, 3H); 7.11 (t, 1H); 7.01 (d, 1H); 6.53 (d, 1H); 4.40 (m, 1H); 2.80 (s, 3H); 1.60 (d, 3H). HRMS (ESI): (M+H)+ calculated 625.1833, found 625.1828.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.P(O)(O)O.C(N(CC)CC)C.[OH-].[Na+]>O>[CH2:1]([NH:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NCc1ccccc1
Agent: OP(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Product: c1ccc(CNCc2ccccc2)cc1
Yield: 98 %

Procedure:
The imine from benzaldehyde and benzylamine (19.5 g; 0.1 mole) was heated with phosphorous acid (8.2 g; 0.1 mole) and triethylamine (10.1 g; 0.1 mole) for 2 hours at reflux (125°-130°). After cooling to 90° the reaction mixture was diluted with water (50 ml), basified (NaOH) and extracted with chloroform. The extract was concentrated by evaporation of the chloroform and triethylamine to yield dibenzylamine 19.3 g (98% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH2:20])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:35])[CH2:30][CH2:31][C:32](O)=[O:33])=[CH:25][CH:24]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:32](=[O:33])[CH2:31][CH2:30][C:29]([C:26]3[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=3)=[O:35])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCC(=O)c1ccc(Cl)cc1)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 24 h
Yield: 42 %

Procedure:
(S)-N-[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl amine (0.100 gm, 0.00034 moles) was taken up in 1:1 THF-water mixture (20 ml). To this was added 4-(4-chlorophenyl)-4-oxobutanoic acid (0.072 g, 0.00034 moles and HOBt (0.046 g, 0.00034 moles). The resulting mixture was cooled to 0° C., and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.071 gm, 0.00037 moles) was added. The resulting mixture was allowed to warm to room temperature and then stirred for 24 hr. The reaction mixture was concentrated and 2 ml of saturated aqueous sodium bicarbonate solution was added, stirred for 15 min and then extracted with dichloromethane. The organic layer was separated and evaporated off. The residue was chromatographed over silica gel (100-200 mesh, 20 g) and eluted with mixture of ethyl acetate:hexane, and finally with ethyl acetate. The combined fractions were concentrated to give (0.070 gm, 42%) of the title compound as a white solid.
Reaction SMILES: [OH-].[Ca+2].[OH-].[CH2:4]([O:7][C:8]([N:10]1[CH2:14][C@H:13](OS(C)(=O)=O)[CH2:12][C@H:11]1[CH2:20][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[O:9])[CH:5]=[CH2:6].[C:26]([SH:29])(=[O:28])[CH3:27]>CC(C)CC(=O)C>[C:26]([S:29][C@@H:13]1[CH2:14][N:10]([C:8]([O:7][CH2:4][CH:5]=[CH2:6])=[O:9])[C@H:11]([CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH2:12]1)(=[O:28])[CH3:27]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1Cn1ccnc1
Reactant: CC(=O)S
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1Cn1ccnc1

Procedure:
To a solution of calcium hydroxide (2.25 g) and (2S,4R)-1-allyloxycarbonyl-2-(imidazol-1-yl)methyl-4-methanesulfonyloxypyrrolidine (10 g) in 4-methyl-2-pentanone (60 ml) was added dropwise thioacetic S-acid (4.38 ml) with stirring below 45° C. The solvent (18 ml) of the mixture was removed under reduced pressure at 40°-45° C. The resulting suspension was heated at 80°-85° C. for 2 hours. After cooling, water (20 ml) and ethyl acetate (20 ml) was added to the reaction mixture The insoluble material was filtered off and washed with ethyl acetate (30 ml). The filtrate and washing were combined. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(imidazol-1-yl)methylpyrrolidine (7.94 g).
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([NH2:8])[CH:3]=1.CCN(C(C)C)C(C)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>ClCCCl>[Br:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([NH:8][S:18]([CH3:21])(=[O:20])=[O:19])[CH:3]=1
Reactant: Cn1nc(N)cc1Br
Reactant: CS(=O)(=O)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(NS(C)(=O)=O)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.8 %

Procedure:
5-Bromo-1-methyl-1H-pyrazol-3-amine (500 mg, 2.84 mmol) and DIPEA (2.47 mL, 14.2 mmol) were stirred in anhydrous 1,2-dichloroethane (8 mL) at room temperature, then mesyl chloride (550 μL, 7.1 mmol) in 1,2-dichloroethane (1.5 mL) was added dropwise. The mixture was stirred at room temperature for 3 h, then partitioned between DCM and water. The organic phases were separated and washed with brine, then dried over sodium sulfate and concentrated. To the resulting orange/brown solid was added 1M tetrabutylammonium fluoride in THF (10.5 mL) and the mixture was heated at reflux for 4 h. The reaction mixture was concentrated and diluted with DCM (40 mL), then washed with water (4×25 mL), followed by brine (25 mL). The organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with 35-50% EtOAc in heptane followed by 5-10% MeOH in DCM, to afford the title compound (388 mg, 54%) as a white solid. δH (250 MHz, CDCl3) 6.33 (s, 1H), 3.85 (s, 3H), 3.02 (s, 3H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[N:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[N:14][CH:13]=1.Cl>>[CH2:1]([O:8][C:12]1[N:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[N:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cncc(Cl)n1
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: O=C(O)c1cncc(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 1 mL of benzyl alcohol cooled in an ice bath was added 0.1 g of 60% sodium hydride oil dispersion. After 15 min., 0.1 g of 6-chloro-2-pyrazinoic acid was added. The mixture was stirred at room temperature for 1 h, then acidified with 2 mL of 1N HCl. The mixture was cooled in an ice bath and the white precipitate collected by filtration. Drying under vacuum gave 0.132 g of 6-benzyloxy-2-pyrazinoic acid: mp 160°-162° C.; 1H NMR (400 MHz, CDCl3) 9.00 (s, 1H), 8.56 (s, 1H), 7.49-7.36 (m, 5H), 5.46 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:10][NH:11][C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=3)=[N:10][N:11]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:12]=2[C:13]([F:16])([F:14])[F:15])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c1C(F)(F)F
Yield: 33.6 %

Procedure:
4-(4-Fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole (Example 1, Step 3) (2.11 g, 5.5 mmol) and ethyl bromoacetate (1.09 g, 6.5 mmol) were stirred vigorously in 15 mL dry DMF with finely powdered potassium carbonate (1.38 g, 10 mmol) under nitrogen at 25° C. for 3 hours. The mixture was diluted with ethyl acetate and filtered to remove solids. The organic filtrate was washed with two portions of water followed by brine, dried over MgSO4 and concentrated in vacuo. The desired isomer was isolated by chromatography on silica gel, using 10% ethyl acetate/90% heptane as the eluant, to give ethyl [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate as a white solid (0.87 g, 34%). Elemental analysis for C21H18N2F4SO4Calc'd: C, 53.62, H, 3.86, N, 5.96, S, 6.82. Found: C, 53.69, H, 3.97, N, 5.87, S, 7.05.
Reaction SMILES: C([O:5][C:6](=[O:21])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:20])[CH2:13][CH2:14][S:15][C:16]([NH:18][CH3:19])=[S:17])(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[CH3:19][NH:18][C:16]([S:15][CH2:14][CH2:13][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:21])=[O:5])=[O:20])=[S:17]
Reactant: CNC(=S)SCCC(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CNC(=S)SCCC(=O)N1CCC[C@H]1C(=O)O

Procedure:
1-[3-[[(Methylamino)thiocarbonyl]thio]propanoyl]-L-proline tertbutyl ester (0.98 g) is dissolved in a mixture of anisole (3.6 ml) and trifluoroacetic acid (7.5 ml). After one hour at room temperature the mixture is concentrated to dryness in vacuo and the residue precipitated from ether-hexane three times. This material is chromatographed on a column of silica gel with a solvent mixture of benzene-acetic acid (75:25) to yield 1-[3-[[(methylamino)thiocarbonyl]thio]propanoyl]-L-proline, Rf = 0.4 [silica gel-benzene:acetic acid (75:25)]. The dicyclohexylammonium salt has m.p. 127°-129°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[O:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH3:22].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:21][CH3:22])=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: CCI
Reactant: COC(=O)c1ccc(O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)OC)c(OC)c1
Temperature: 50 °C
Yield: 496.4 %

Procedure:
To a solution of 4-hydroxy-2-methoxybenzoic acid methyl ester (4.17 g, 22 mmol) in DMF (50 ml) under argon was added potassium carbonate (6.33 g, 4.6 mmol) followed by iodoethane (7.15 g, 4.6 mmol). The mixture was then heated to 50° C. under argon for 12h. On cooling the mixture was poured into a large excess of water and extracted with ether. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a brown oil (4.8 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[O:27][CH:28]=[CH:29][N:30]=1>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[O:27][CH:28]=[CH:29][N:30]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccccc1-c1ncco1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc(CN2CCN(c3ccccc3-c3ncco3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
A solution of N-benzylpiperazine (3.56 g, 20.2 mmol) in 25 mL of THF was cooled to 0° C. and then n-butyllithium was added. The mixture was stirred at 0° C. for 30 minutes and at room temperature for an additional hour. The mixture was cooled to 0° C. and then 2-fluoro-1-oxazol-2-ylbenzene (1.1 g, 6.75 mmol) was slowly added. The mixture was allowed to warm to room temperature and stirred at room temperature for 90 minutes. The mixture was quenched with water and the aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The combined extract was washed with brine, dried (MgSO4) and concentrated. The residue was purified on silica gel by column chromatography eluting with hexanes/ethyl acetate (10:1) to give 4-benzyl-1-(2-oxazol-2-ylphenyl)piperazine (0.805 g, 2.52 mmol).
Reaction SMILES: [Na].[OH:2][N:3]=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:13]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14].C(=O)([O-])O.[Na+]>O.CC(C)=O>[CH2:16]([O:15][C:13]([O:2][N:3]=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:14])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)COC(=O)Cl
Reactant: CCOC(=O)C(C#N)=NO
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(C#N)=NOC(=O)OCC(C)C
Temperature: 20 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of sodium salt of ethyl 2-hydroxyimino-2-cyanoacetate (16.4 g) in water (100 ml), isobutyl chloroformate (13.7 g) and acetone (10 ml) are added, and the resulting mixture is stirred at a temperature lower than 20°C. After adjusting pH to 7 with the addition of an aqueous solution of sodium hydrogencarbonate, stirring is continued for 3 hours. The reaction mixture is extracted with ethyl acetate, and the organic layer is washed with water, dried and concentrated. The residue is crystallized with the addition of petroleum ether and collected by filtration. Recrystallization from petroleum ether containing a small amount of ethyl acetate affords ethyl 2-isobutoxycarbonyloxyimino-2-cyanoacetate (14.1 g) as scales. M.P. 60 to 62°C.
Reaction SMILES: [OH:1][C@@H:2]([CH2:16][CH3:17])[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])O[CH:9]=[CH:8]2.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH2:34])[CH:23]=[CH:24][C:25]=1[N:26]1[CH2:32][CH2:31][CH2:30][N:29]([CH3:33])[CH2:28][CH2:27]1>>[OH:1][C@@H:2]([CH2:16][CH3:17])[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:34]([C:22]1[CH:23]=[CH:24][C:25]([N:26]3[CH2:32][CH2:31][CH2:30][N:29]([CH3:33])[CH2:28][CH2:27]3)=[C:20]([O:19][CH3:18])[CH:21]=1)[CH:9]=[CH:8]2
Reactant: COc1cc(N)ccc1N1CCCN(C)CC1
Reactant: CC[C@H](O)COc1ccc2c(=O)occc2c1
Product: CC[C@H](O)COc1ccc2c(=O)n(-c3ccc(N4CCCN(C)CC4)c(OC)c3)ccc2c1

Procedure:
6-((S)-2-Hydroxy-butoxy)-isochromen-1-one and 3-methoxy-4-(4-methyl-[1,4]diazepan-1-yl)-phenylamine were reacted according to Method AJ. In this way the product was obtained with molecular weight 451.57 (C22H33N3O4); MS (ESI): 452 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][CH:15]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=2)[C:16]2[N:17]=[N:18][N:19]([CH2:21][Si](C)(C)C)[CH:20]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][CH:15]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=2)[C:16]2[N:17]=[N:18][N:19]([CH3:21])[CH:20]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CC(=O)NC(c2ccc(F)c(F)c2)c2cn(C[Si](C)(C)C)nn2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(C(NC(=O)Cc2ccc(C(C)(C)C)cc2)c2ccc(F)c(F)c2)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a 10 ml round bottom flask containing a solution of 2-(4-tert-butylphenyl)-N-((3,4-difluorophenyl){1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}-methyl)acetamide (0.062 mg, 0.132 mmol) in 1.0 ml of anhydrous THF at rt was added 1.0N tetrabutylammonium fluoride in THF (0.145 ml, 0.145 mmol). The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum. Purification by preparative HPLC (20-90% CH3CN/H2O over 30 min, 0.05% added TFA, C18 column) to afford 0.046 g (88%) of the title compound. Purification by super fluid (CO2/MeOH) chiral column yielded first enathiomer (19 mg) (36.2%), and second enathiomer (21 mg) (40%) 1H NMR (CDCl3, 400 MHz) δ 7.359 (m, 2H), 7.307 (s, 1H), 7.183 (m, 2H), 7.009 (m, 3H), 6.769 (d, J=7.32 Hz, 1H), 6.216 (d, J=7.57 Hz, 1H), 4.059 (s, 3H), 3.581 (ABq, J=15.75 Hz, 2H), 1.311 (s, 9H). ES-MS [M+1]+: 399.2.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:8]([CH:18]=1)[C:9]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:10].ClC1C=CC(S(O[CH2:38][C@@H:39]2[CH2:43][CH2:42][CH2:41][N:40]2[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])(=O)=O)=CC=1.O>CS(C)=O>[C:21]1([CH2:20][O:19][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:38][C@@H:39]3[CH2:43][CH2:42][CH2:41][N:40]3[C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])=[CH:18][C:8]=2[C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:10])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(Nc1cccnc1)c1cc(O)ccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (36.0 mg, 1.50 mmol) was added to a solution of 5-hydroxy-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 29; 400 mg, 1.25 mmol) in dimethylsulfoxide (8 ml) at 0° C., and the mixture was stirred at room temperature for 1 h. 1,1-Dimethylethyl (2S)-2-({[(4-chlorophenyl)sulfonyl]oxy}methyl)-1-pyrrolidinecarboxylate (444 mg, 1.25 mmol) in dimethylsulfoxide (7 ml) was added to the solution dropwise, and the mixture was stirred at 75° C. for 18 h. The mixture was poured into water (100 ml), extracted thoroughly with ethyl acetate. The organic layer was dried, and concentrated to obtain a crude product, which was purified by chromatography on silica gel (dichloromethane/methanol=50:1) to yield the title compound as a yellow oil. 0.60 g.
Reaction SMILES: [NH2:1][C:2]1[S:14][C:5]2[CH2:6][N:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][C:4]=2[C:3]=1[C:15]([O:17]CC)=O.C([O-])=O.[NH4+].[CH:24]([NH2:26])=O>O>[O:17]=[C:15]1[NH:26][CH:24]=[N:1][C:2]2[S:14][C:5]3[CH2:6][N:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][C:4]=3[C:3]1=2
Reactant: CCOC(=O)c1c(N)sc2c1CN(C(=O)OCC)C2
Reactant: NC=O
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: CCOC(=O)N1Cc2sc3nc[nH]c(=O)c3c2C1
Temperature: 140 °C
Yield: 52 %

Procedure:
Diethyl 2-amino-4,6-dihydro-5H-thieno[2,3-c]pyrrole-3,5-dicarboxylate from Example 19A (3.60 g, 12.7 mmol) was dissolved in formamide (72 mL), and ammonium formiate (2.11 g, 20.3 mmol) was added. The mixture was heated to 140° C. overnight, then diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was removed in vacuo. The precipitate in the aqueous layer was collected by suction filtration and combined with the organic extracts. The product was purified by column chromatography on silica gel (eluent: DCM/MeOH 100:3) and subsequently triturated with tert-butyl methyl ether to yield 1.74 g (52%) of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>>[N+:17]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][N:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=1)[S:21]([CH3:20])(=[O:23])=[O:22])([O-:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CSc1cccc(NCc2cccc([N+](=O)[O-])c2)c1
Product: CSc1cccc(N(Cc2cccc([N+](=O)[O-])c2)S(C)(=O)=O)c1

Procedure:
The product of Example 4 is treated with methane sulfonyl chloride according to known procedures to yield the title product (Compound No. 6).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:25])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[C:12]([C:10]1[N:11]=[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])[C:7]([OH:25])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[C:9]=12)#[N:13]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(F)cc2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccn(Cc3ccc(F)cc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 7-cyano-1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 369 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[C:21]([CH2:22][OH:23])=[CH:20][CH:19]=[CH:18][N:17]=1.CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:23][CH2:22][C:21]1[C:16]([O:15][C:3]2[CH:4]=[CH:5][C:6]3[N:7]([CH2:11][CH:12]4[CH2:13][CH2:14]4)[N:8]=[N:9][C:10]=3[C:2]=2[Br:1])=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cccnc1Oc1ccc2c(nnn2CC2CC2)c1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cccnc1Oc1ccc2c(nnn2CC2CC2)c1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(2-{[4-bromo-1-(cyclopropylmethyl)-1H-1,2,3-benzotriazol-5-yl]oxy}pyridin-3-yl)methanol (195) (1 g, 2.62 mmol, 1.0 equiv.) and Et3N (1.1 ml, 7.85 mmol, 3.0 equiv.) in DCM (13 ml) were cooled to 0° C., followed by MsCl (265 ul, 3.40 mmol, 1.3 equiv.), then stirred @ 0° C. for 1 hour. The reaction mixture then quenched with NaHCO3(sat) and extracted with DCM (2×40 ml). The combined DCM layer was washed with brine and dried over Na2SO4, filtered and concentrated down solvent. LRMS m/z (M+H) 486.8 and 488.8 found, 487.0 and 489.0 required.