Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11](/[CH:22]=[C:23](\[C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)/[C:24]([OH:26])=[O:25])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC([O-])=O.[Na+]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([CH2:22][CH:23]([C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)[C:24]([OH:26])=[O:25])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(-c2[nH]c(/C=C(/C(=O)O)c3cccc(C)c3)nc2-c2ccc(Cl)c(Cl)c2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2[nH]c(CC(C(=O)O)c3cccc(C)c3)nc2-c2ccc(Cl)c(Cl)c2)cc1
Yield: 24.7 %

Procedure:
A stirred solution of (E)-3-[4-(3,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-m-tolyl-acrylic acid (Example 17; 50 mg, 0.084 mmol), p-toluenesulfonylhydrazide (0.24 g, 1.26 mmol) and NaOAc (0.10 g, 1.26 mmol) in EtOH (1.0 mL) was heated to 85° C. for 16 h. The reaction mixture was cooled and then purified directly by reversed-chromatography (Method B) to afford the title compound (10 mg, 20%). HPLC: Rt=1.19 (Method D). MS (ESI): mass calculated for C26H22Cl2N2O3, 480.10; m/z found, 481.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.54 (d, J=2.0 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.34-7.29 (m, 2H), 7.27 (dd, J=8.3, 2.0 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 7.17-7.10 (m, 3H), 6.96-6.91 (m, 2H), 4.40 (dd, J=10.1, 5.8 Hz, 1H), 3.86 (s, 3H), 3.61 (dd, J=14.9, 10.1 Hz, 1H), 3.29 (dd, J=14.9, 5.8 Hz, 1H), 2.34 (s, 3H).
Reaction SMILES: [CH:1]([OH:3])=O.OO.[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[C:14]1C[CH2:17][CH2:16][CH:15]=1>O>[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[CH:14]1[CH2:15][CH2:16][CH2:17][C:1]1=[O:3]
Reactant: O=CO
Reactant: Cc1ccc(C2=CCCC2)c(C)c1
Agent: OO
Solvent: O
Product: Cc1ccc(C2CCCC2=O)c(C)c1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of 18 mL of 96% formic acid and 2 mL of water was added 4.5 mL of 30% hydrogen peroxide and the resulting solution was warmed to 40° C. for 10 minutes. The 1-(2,4-dimethyl-phenyl)cyclopentene (6 g) was slowly added with ice-bath cooling to maintain the internal temp at 35-40° C. The mixture was stirred at room temperature for 4 hours, diluted with water, and extracted with ether. The ether was washed with aqueous sodium bicarbonate and brine, dried, and evaporated. Purification of the residue by flash chromatography (15% ethyl acetate/hexane) afforded 2.5 g of 2-(2,4-dimethyl-phenyl)-cyclopentanone as an oil.
Reaction SMILES: [Na].[C:2]([S:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]1)(=O)[CH3:3].[N+:13](CCOC(=O)C)([O-:15])=[O:14]>C(O)C>[N+:13]([CH2:3][CH2:2][S:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]1)([O-:15])=[O:14]
Reactant: CC(=O)OCC[N+](=O)[O-]
Reactant: CC(=O)SC1C=CCCCC1
Agent: [Na]
Solvent: CCO
Product: O=[N+]([O-])CCSC1C=CCCCC1
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To 40 ml of absolute ethanol was added 1.38 g (0.060 gram atom) metallic sodium. When the reaction was completed, 10.2 g (0.060 mole) of 3-acetylmercaptocycloheptene in 20 ml of absolute ethanol was added and the reaction mixture was brought up to reflux for 15 minutes. The solution was then cooled to 0° and 7.98 g (0.060 mole) of 1-nitro-2-acetoxyethane in 20 ml absolute ethanol was added. The reaction was allowed to proceed for 3.0 hours at 0° and then was partitioned between 1N HCl and methylene chloride. The aqueous phase was further extracted with methylene chloride. The organic phases were pooled, dried over sodium sulfate, and evaporated to afford 12 g (99%) of pure 3-[2-nitroethylthio]cycloheptene as a colorless oil.
Reaction SMILES: C(=O)([O-])O[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:11](=O)([O:14]C1C=CC=CC=1)[O:12][CH3:13].C(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>>[C:11]([O:12][CH3:13])(=[O:14])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C([O-])Oc1ccccc1
Reactant: COC(=O)Oc1ccccc1
Agent: O=C(Oc1ccccc1)Oc1ccccc1
Product: COC(=O)c1ccccc1
Yield: 41 %

Procedure:
The same procedures as in Example 1 were used, except that the reaction temperature of the phenyl carbonate preparation step was 210° C. As a result, the yield of methyl phenyl carbonate was 17%, and the yield of diphenyl carbonate was 24%. Furthermore, at the same time, methyl benzoate was produced as a by-product with a yield of 41% (the yield was based on phenyl benzoate).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@H:9]([OH:32])[CH2:10][N:11]([S:20]([C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1)(=[O:22])=[O:21])[CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][CH2:15][C:16]#[N:17])(C)(C)C.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[NH2:7][C@@H:8]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@H:9]([OH:32])[CH2:10][N:11]([CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][CH2:15][C:16]#[N:17])[S:20]([C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1)(=[O:21])=[O:22]
Reactant: CC(C)(CCC#N)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CCC#N)CN(C[C@@H](O)[C@@H](N)Cc1ccccc1)S(=O)(=O)c1ccc2c(c1)OCO2
Reaction time: 0.5 h

Procedure:
A solution of {(1S,2R)-3-[(Benzo[1,3]dioxole-5-sulfonyl)-(4-cyano-2,2-dimethyl-butyl)-amino]-1-benzyl-2-hydroxy-propyl}-carbamic acid tert-butyl ester (0.075 g, 0.13 mmol) in CH2Cl2 at ambient temperature was treated with TFA. After stirring 30 min solvent was removed in vacuo to give desired product as a white solid which was used directly in the next step.
Reaction SMILES: C(=O)=O.C([O:6][C:7](=O)/[CH:8]=[CH:9]/[C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])[CH2:12][CH2:11]1)C.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.CO>[C:23]([O:22][C:20](=[O:21])[N:18]([CH2:17][CH2:16][C@H:13]1[CH2:12][CH2:11][C@H:10](/[CH:9]=[CH:8]/[CH2:7][OH:6])[CH2:15][CH2:14]1)[CH3:19])([CH3:24])([CH3:26])[CH3:25]
Reactant: CCOC(=O)/C=C/[C@H]1CC[C@H](CCN(C)C(=O)OC(C)(C)C)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CO
Product: CN(CC[C@H]1CC[C@H](/C=C/CO)CC1)C(=O)OC(C)(C)C
Temperature: -75 °C
Reaction time: 2 h

Procedure:
To a dry ice-cooled solution of 4 g (11.8 mmol) trans-3-{4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexyl}-(E)-acrylic acid ethyl ester (example 11.10) in 50 ml of tetrahydrofuran was added at −75° C. to −63° C. within 15 minutes 23.6 ml (28.3 mmol) of a solution of diisobutyl-aluminium hydride (1.2M in toluene). After the reaction mixture was stirred for 2 hours at −75° C., 20 ml of methanol was added at −75° C. to this mixture. The temperature was raised to 20° C. and 20 ml 1N hydrogen chloride solution was added. The reaction mixture was partitioned between ether, 1N hydrogen chloride solution, sodium hydrogen carbonate solution and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure giving 3.61 g of trans-{2-[4-(3-hydroxy-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic acid tert-butyl ester as slightly yellow viscous oil, MS: 298 (MH+).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl.[NH:37]1[CH2:42][CH2:41][O:40][CH:39]([C:43]([OH:45])=[O:44])[CH2:38]1>C(Cl)Cl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:37]3[CH2:42][CH2:41][O:40][CH:39]([C:43]([OH:45])=[O:44])[CH2:38]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)C1CNCCO1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCOC(C(=O)O)C3)ccc2n1CC1CCC(F)(F)CC1
Yield: 75.1 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (1.6 g, 4 mmol), N,N-diisopropylethylamine (3.5 mL, 20 mmol) and morpholine-2-carboxylic acid hydrochloride (1.0 g, 6 mmol) in methylene chloride (10 mL). Obtained 1.5 g of crude product which was carried over to step A. 1H NMR (400 MHz, METHANOL-D4) δ 1.53 (d, J=13.67 Hz, 2 H), 1.59 (s, 12 H), 1.63-1.78 (m, 6 H), 1.98-2.12 (m, 3 H), 3.22 (q, J=7.36 Hz, 1 H), 3.72 (m, 1 H), 4.42 (d, J=7.42 Hz, 2 H), 7.69 (d, J=8.40 Hz, 1 H), 7.81 (d, J=8.40 Hz, 1 H), 8.05 (s, 1 H).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[N:9]([C:16](=[O:19])[CH2:17][CH3:18])[CH2:10][CH2:11][N:12]([CH:14]=[O:15])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O=O>>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][N:12]([CH:14]=[O:15])[CH2:11][CH2:10][N:9]1[C:16](=[O:19])[CH2:17][CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(=O)N1CCN(C=O)C=C1C(=O)NC(C)(C)C
Agent: O=O
Product: CCC(=O)N1CCN(C=O)C[C@H]1C(=O)NC(C)(C)C
Reaction time: 8 h
Yield: 104.8 %

Procedure:
16.1 g (60.2 mmol) of 4-formyl-1-propionyl-1,4,5,6-tetrahydropyrazine-2-carboxylic acid tert-butylamide, 19.5 mg (35.9 μmol) of 1-[1(R)-(di-tert-butylphosphino)-ethyl]-2(S)-(diphenylphosphino)ferrocene and 11.1 mg (29.6 μmol) of bis(bicyclo[2.2.1]hepta-2,5-diene)rhodium(I) tetrafluoroborate were placed in an autoclave, oxygen being excluded. After flushing with argon, 80 ml of oxygen-free methanol was added. Hydrogenation was carried out at an initial pressure of 12 bar and a temperature of 90° C. for 8 hours. The autoclave was depressurized and flushed with nitrogen. The solvent of the reaction mixture was completely distilled off to give 17.00 g (94%) of the title product. GC analysis showed a conversion of 99 percent. After cleavage of the protecting groups with hydrochloric acid, the enantioselectivity of the hydrogenation was determined by GC analysis, giving an ee of 96.5 percent. The melting point of the title compound was: 132.1° to 134.3° C. Other data concerning the title compound was:
Reaction SMILES: SCCO.C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=O.[Na+].[Na+].CCCCCCCCCCCCOS([O-])(=O)=O.[Na+].CCC(COC(C(N(CC[NH+](C)C)C)=O)(C1C=CC=CC=1)C1C=CC=CC=1)CC.[Cl-].[CH3:75][C:76]1[C:82]2[CH:83]=[CH:84][C:85]([O:87][C@@H]3O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]3O)=[CH:86][C:81]=2[O:80][C:78](=[O:79])[CH:77]=1>C([O-])([O-])=O.[Na+].[Na+]>[CH3:75][C:76]1[C:82]2[CH:83]=[CH:84][C:85]([OH:87])=[CH:86][C:81]=2[O:80][C:78](=[O:79])[CH:77]=1
Reactant: Cc1cc(=O)oc2cc(O[C@@H]3O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]3O)ccc12
Agent: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Product: Cc1cc(=O)oc2cc(O)ccc12
Reaction time: 1 h

Procedure:
To evaluate the activity of various promoters, GUS fluorescence was assayed by the method of Jefferson (1987). Maturing seeds at 17 DAF were homogenized in GUS extraction buffer (50 mM NaPO4 [pH 7.0], 10 mM 2-mercaptoethanol, 10 mM Na2-EDTA, 0.1% SDS, 0.1% Triton X-100). After centrifugation, 10 μl of the supernatant was mixed with 90 μl of assay buffer containing 1 mM 4-methylumbelliferyl-β-D-glucuronide (MUG). After incubating for one hour at 37° C., 900 μl of 0.2 M Na2CO3 was added to the mixture to terminate the reaction. Values obtained using a fluorometer were compared with those obtained from serial dilutions of 4-methylumbelliferone (4MU). The protein amount was determined using a BIO-RAD® Protein Assay kit, which is based on the Bradford method (Bradford, M., Anal. Biochem. 72, 248 (1976)), with serum albumin as the standard. Three seeds were assayed for each transgenic plant.
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].C([Li])CCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:18]=[O:19].[Cl-].[NH4+]>O1CCCC1.C(#N)C.CCCCCC>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]([OH:19])[CH2:2][C:1]#[N:4])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: CC(C)NC(C)C
Reactant: COc1ccc(C=O)cc1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC#N
Product: COc1ccc(C(O)CC#N)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (0.67 g, 6.62 mM) in dried tetrahydrofuran (5 ml) was cooled to −78° C. A hexane solution of n-butyllithium (6.62 mM) was dropped into this solution, then this was stirred at that temperature for 30 minutes. Next, acetonitrile (0.27 g, 6.62 mM) was dropped into this solution and the result stirred for a further 30 minutes, then a solution of 3,4-dimethoxybenzaldehyde (1.00 g, 6.02 mM) in dried tetrahydrofuran (5 ml) was added and the mixture stirred at that temperature for 4 hours. An aqueous ammonium chloride was poured into the obtained solution, which was warmed to room temperature and extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was removed in vacuo to obtain a crude product (1.25 g) of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile as a yellow oil. The crude product thus obtained had sufficient purity without purification, therefore could be used for the next reaction as it was.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:37]/[O:38][C:39]([C:42]([OH:44])=[O:43])([CH3:41])[CH3:40])/[C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:32]([O-:34])=[O:33])=[C:15]([CH2:18][N+:19]4[N:23]5[CH2:24][CH2:25][CH2:26][NH:27][C:22]5=[C:21]([CH2:28][NH:29]C=O)[CH:20]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1>Cl>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:37]/[O:38][C:39]([C:42]([OH:44])=[O:43])([CH3:40])[CH3:41])/[C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:32]([O-:34])=[O:33])=[C:15]([CH2:18][N+:19]4[N:23]5[CH2:24][CH2:25][CH2:26][NH:27][C:22]5=[C:21]([CH2:28][NH2:29])[CH:20]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cc(CNC=O)c4n3CCCN4)CS[C@H]12)c1nsc(N)n1)C(=O)O
Agent: Cl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cc(CN)c4n3CCCN4)CS[C@H]12)c1nsc(N)n1)C(=O)O
Yield: 38.6 %

Procedure:
A solution of 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[3-(formamidomethyl)-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio]methyl-3-cephem-4-carboxylate (130 mg) in 10% aqueous hydrochloric acid (4.36 ml) was stirred at room temperature for 6 hours. The reaction mixture was purified by preparative HPLC utilizing ODS column. The eluate containing a desired product was concentrated to about 30 ml in vacuo. The concentrate was adjusted to about pH 3 with concentrated hydrochloric acid and chromatographed on Diaion® HP-20 (Mitsubishi Chemical Corporation) eluting with 30% aqueous 2-propanol. The eluate was concentrated to about 30 ml in vacuo and lyophilized to give 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(3-aminomethyl-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate (48 mg) as an amorphous solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O.CO.C([O-])(O)=O.[Na+]>CN(C=O)C>[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1
Reactant: OB(O)c1ccco1
Reactant: Nc1nc(Br)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccco2)cs1
Temperature: 70 °C

Procedure:
4-Bromo-thiazol-2-ylamine (100 mg, 0.34 mmol) was combined with 57 mg (0.51 mmol) of 2-furan boronic acid. To this mixture was added 5 mL of MeOH, 1 mL of sat. NaHCO3 (aq), and 0.8 mL of DMF. Reaction mixture was degassed and Pd[P(Ph)3]4 (25 mg) was added. Reaction mixture was heated at 70° C. for 7 hours. The reaction mixture was brought to room temperature and filtered. The filtrate was evaporated and purified using reverse phase HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:8]([CH3:10])[CH3:9])[S:5][CH:6]=1.C(NC(C)C)(C)C.[Li].[CH:19](N1CCCCC1)=[O:20]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:8]([CH3:10])[CH3:9])[S:5][C:6]=1[CH:19]=[O:20]
Reactant: O=CN1CCCCC1
Reactant: CN(C)Cc1cc(Br)cs1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CN(C)Cc1cc(Br)c(C=O)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To (4-bromo-thiophen-2-ylmethyl)-dimethyl-amine [4.08 g, 18.5 mmol, Intermediate (1)] in tetrahydrofuran (40 mL) at 0° C. and under a nitrogen atmosphere is added Lithium diisopropylamine (2.0M in tetrahydrofuran pentanes from Aldrich chemicals, 20.4 mmol). The orange solution is stirred at 0° C. for 30 minutes. Then N-formylpiperidine is added (2.5 mL, 22.2 mmol). The mixture is allowed to stir at 0° C. for 1 hour. It is diluted with ethyl acetate washed with brine, dried over magnesium sulfate and concentrated. The residual orange oil was chromatographed through silica gel (dichloromethane-1.0M ammonia in methanol, 95:05 as eluant) to produce 3-bromo-5-dimethylaminomethyl-thiophene-2-carbaldehyde [4.4 g, Intermediate (2)] as an orange oil. LC/MS: RT=0.47 minutes, 247.98 m/e (M+H).
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([CH:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20](=[O:28])(=[O:27])[NH:19]2)=[CH:9]1)(C)(C)C.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][N:19]2[CH:18]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=4)[N:8]([CH2:7][C:6]([OH:5])=[O:29])[CH:9]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20]2(=[O:27])=[O:28])=[CH:33][CH:32]=1
Reactant: Cc1ccc2c(c1)c(C1NS(=O)(=O)c3ccccc31)cn2CC(=O)OC(C)(C)C
Reactant: Fc1ccc(CBr)cc1
Product: Cc1ccc2c(c1)c(C1c3ccccc3S(=O)(=O)N1Cc1ccc(F)cc1)cn2CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 2, step c) and 4-fluorobenzyl bromide. 1H NMR (DMSO-d6) 8.00 (d, J=6.6 Hz, 1H), 7.66-7.58 (m, 2H), 7.39 (s, 1H), 7.24 (dd, J=3.0, 8.4 Hz, 2H), 7.22-7.20 (m, 1H), 7.04 (t, J=8.8 Hz, 2H), 6.90 (d, J=8.1 Hz, 1H), 6.76 (s, 1H), 5.75 (s, 1H), 4.94 (s, 2H), 4.50 (d, J=15.9 Hz, 1H), 3.97 (d, J=15.9 Hz, 1H), 2.16 (s, 3H); MS: ESI (negative): 463 (M−H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][S:45]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:47])=[O:46])[CH:29]=3
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2)c1ccccc1
Yield: 42 %

Procedure:
The desired compound was prepared according to the procedure of Example B136, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and benzenesulfonyl chloride as the starting materials in 42% yield. LCMS for C24H21ClN5O2S (M+H)+: m/z=478.1. 1H NMR (400 MHz, DMSO-d6): δ 10.24 (s, 1H), 9.55 (s, 1H), 9.50 (s, 1H), 8.15 (s, 1H), 7.76 (m, 3H), 7.50 (m, 3H), 7.40 (m, 1H), 7.10 (dd, 1H), 6.94 (m, 1H), 6.88 (m, 1H), 6.80 (m, 1H), 6.69 (m, 1H), 2.74 (m, 4H).
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]([C:20]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]4[O:39][N:38]=[C:37]([CH3:40])[C:36]=4[CH2:41][NH:42][CH2:43][CH:44]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[CH3:45])=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH2:22][CH2:21]1)=[O:19])[CH3:16].C=O>>[CH2:15]([O:17][C:18]([C:20]1([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]4[O:39][N:38]=[C:37]([CH3:40])[C:36]=4[CH2:41][N:42]([CH3:1])[CH2:43][CH:44]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH3:45])=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)[CH2:21][CH2:22]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNCC(C)c4ccccc4)cc3)cc2)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN(C)CC(C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 67, Step 1, using sodium triacetoxyborohydride instead of sodium borohydride and the following starting materials: 1-(4′-{3-methyl-4-[(2-phenyl-propylamino)-methyl]-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester and formaldehyde.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:4]=1[NH2:5])#[N:2].[N:14]([O-])=O.[Na+]>Cl>[NH2:2][C:1]1[C:3]2[C:4](=[CH:6][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:8][CH:9]=2)[NH:5][N:14]=1
Reactant: O=N[O-]
Reactant: N#Cc1ccc(C(F)(F)F)cc1N
Agent: Cl
Agent: [Na+]
Product: Nc1n[nH]c2cc(C(F)(F)F)ccc12

Procedure:
To a mixture of 18.6 g. of 2-cyano-5-trifluoromethylaniline and 120 ml. of concentrated hydrochloric acid is added dropwise 8.0 g. of sodium nitrite in aqueous solution. The resulting diazo solution is added dropwise to 152 g. of stannous chloride in concentrated hydrochloric acid at 0° C. After allowing the mixture to stand for several hours at 0° C., it is filtered. The solid is treated with boiling water and the solution is made alkaline. The precipitate is recrystallized from benzene to give 3-amino-6-trifluoromethylindazole, M.P. 168°-169° C.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:16])([F:15])[C:5]1[C:10]([C:11](OC)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1>C1COCC1>[F:16][C:4]([F:3])([F:15])[C:5]1[C:10]([CH2:11][OH:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: COC(=O)c1cccnc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1cccnc1C(F)(F)F
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a suspension of sodium borohydride (0.24 g, 6.32 mmol) in anhydrous THF (40 mL) at 0° C. was added dropwise a solution of methyl 2-(trifluoromethyl)pyridine-3-carboxylate (650 mg, 3.16 mmol) in THF (50 mL). After stirring for 1 hour, the reaction mixture was slowly quenched with 15% NaOH and then diluted with water. Ethyl acetate was added, the reaction mixture was stirred for 10 minutes, and the precipitated white solid was filtered off. The solid was washed with ethyl acetate (3×100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to provide [2-(trifluoromethyl)pyridin-3-yl]methanol as a thick oil (0.505 g, 90% yield), which was used for the next step without any further purification; M+ 177.1.