Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25](OS(C)(=O)=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (30.0 g, 154 mmol), 4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester (52.5 g, 200 mmol) and cesium carbonate (80.1 g, 246 mmol) in anhydrous DMF (400 mL) was heated to 100° C. for 24 h. DMF was removed under high vacuum. The residue was then diluted with water (200 mL) and extracted with EtOAc (3×200 mL). The combined organic phases were washed with water (3×50 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. To the orange-brown oily residue was added diisopropyl ether (300 mL), and the mixture was stirred at 0° C. for 2 h. Colorless crystals separated out that were filtered off and dried in vacuo to give a 1st crop of the title compound. The filtrate was then concentrated in vacuo, the residue was mixed with diisopropyl ether (100 mL), a small amount of the 1s1 crop was added as a seed, and the mixture was stirred overnight. The resulting white precipitate was filtered and dried in vacuo as 2nd crop of the title compound. 1H NMR (300 MHz, CDCl3): δ=1.33 (s, 12H), 1.48 (s, 9H), 1.85-1.93 (m, 2H), 2.15-2.18 (m, 2H), 2.83-2.92 (m, 2H), 4.23-4.39 (m, 3H), 7.76 (s, 1H), 7.84 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.CN(C=O)C.[H-].[Na+].CS(O[CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)(=O)=O>O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[CH:10]=2)[O:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
A 1 L, 1-neck flask was charged with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20.0 g, 103 mmol), and DMF (250 mL). The reaction mixture was cooled to 0° C. and NaH (2.73 g, 108 mmol) (95%) was added. The reaction mixture was stirred at 0° C. for 1 hour. tert-Butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (30.2 g, 108 mmol; prepared as in WO 06/021881) was added and the reaction mixture was heated at 100° C. overnight. The reaction mixture was cooled to ambient temperature and diluted with water. The reaction mixture was extracted with EtOAc, and the organic layer washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified on a Biotage 40S column eluting with EtOAc/Hexane 10% to 25% EtOAc. The product was isolated as a white solid (11.3 g, 29%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](O)=[O:10].B.C1COCC1.O.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10]
Reactant: O=C(O)Cc1ccccc1Br
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCc1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromophenylacetic acid (3.96 g, 18.42 mmol) in 60 mL of anhydrous THF was added slowly at room temperature 24.0 mL (23.95 mmol) of a 1 M solution BH3/THF. After finishing the addition of BH3/THF, the solution was stirred at room temperature for 1 h and then heated at 100° C. for 2 h. After this time, the solution was cooled to room temperature, and a mixture of THF and water (20 mL) was added. Potassium carbonate was then added, along with 60 mL of ether. The organic layer was separated from the mixture, and this layer was washed with water (60 mL), aqueous NaHCO3 (60 mL), and brine (60 mL) before it was dried over magnesium sulfate, filtered, and concentrated to give the crude product. This crude product was purified by silica gel flash chromatography eluting with hexanes and a 5 to 10% gradient of ethyl acetate to give 3.47 g (94%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.57 (d, 1H, J=7.8 Hz), 7.31-7.21 (m, 2H), 7.14-7.08 (m, 1H), 3.90 (app. t, 2H, J=6.6, 6.9 Hz), 3.05 (app. t, 2H, J=6.6 Hz), 1.51 (bs, 1H). 13C NMR (100 MHz, CDCl3): δ 137.76, 132.95, 131.25, 128.19, 127.44, 124.67, 62.04, 39.30. Anal. Calc'd. for C8H9BrO: C, 47.79; H, 4.51. Found: C, 47.75; H, 4.50.
Reaction SMILES: CC[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].CCCCCCCC/C=C\CCCCCCCC(O)=O>>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)O
Yield: 3 %

Procedure:
Fatty acid methyl esters were tested for cold temperature performance as detailed above. The chart below shows the effect of adding long chain saturated fatty acids to C18:1 methyl ester (methyl octadecenoate). Pure C18:1 methyl ester is liquid at −20° C. but addition of C18:0 methyl octadecanoate) raises the observed pour point to as high as +5° C. with as little as 2% C18:0 present in the mixture; at 1% C18:0 the pour point of the mixture is 0° C. Similarly, C16 mixtures with C18:1 dramatically raises the pour point. A mixture of 9% (v/v) C16 methyl ester (methyl hexadecanoate) with 91% C18:1 was solid at −5° C. As little as 3% C16:0 resulted in a solid at −15° C. C14:0 methyl ester (methyl tetradecanoate) at concentrations as low as 1% resulted in a solid at −20° C., and 30% C14:0 was solid at −10° C. Mixtures with C12:0 (methyl dodecanoate) presented an interesting and unexpected result. At levels of C12 between 1% and 5% the mixtures were solid at −20° C., but between 6% and 20% C12 mixtures with C18:1 remained liquid at −20° C. Accordingly, the presence of C12:0 in a biodiesel at 6-20%; or more preferably at 6-10%, has surprising beneficial effects on cold flow properties. Thus, while the longer chain saturated FAMEs significantly raised the pour point of mixtures with C18:1, C14 had a much smaller effect and C12 had almost no effect at concentrations up to 20% (v/v).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([NH2:18])=[N:14][CH:15]=[C:16](I)[C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:19]([N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32])[C:20]#[CH:21].O>CN(C=O)C.C(N(CC)CC)C.[Cu]I>[NH2:18][C:13]1[C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)=[CH:9][S:10][C:11]=2[C:16]([C:21]#[C:20][CH2:19][N:22]2[C:26](=[O:27])[C:25]3[C:24](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]2=[O:32])=[CH:15][N:14]=1
Reactant: C#CCN1C(=O)c2ccccc2C1=O
Reactant: Nc1ccc(-c2csc3c(I)cnc(N)c23)cc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2csc3c(C#CCN4C(=O)c5ccccc5C4=O)cnc(N)c23)cc1
Temperature: 80 °C
Yield: 43.4 %

Procedure:
A suspension of Example 77B (0.6 g, 1.63 mmol) in DMF (3 mL) and triethylamine (2 mL) was degassed by bubbling nitrogen through the suspension for 5 minutes , treated with N-propargylphthalimide (0.45 g, 2.45 mmol), PdCl2(PPh3)4 (57 mg, 0.08 mmol), and CuI (15 mg, 0.08 mmol), then heated to 80° C. for 1 hour. The cooled solution was poured into water, extracted with ethyl acetate and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel using 3% methanol/dichloromethane to provide 300 mg (43% yield) of the desired product. 1H NMR (300 MHz, DMSO-D6) δ ppm 4.72 (s, 2H), 5.37 (s, 2H), 5.86 (s, 2H), 6.66 (d, J=8.14 Hz, 2H), 7.07 (d, J=8.14 Hz, 2H), 7.35 (s, 1H), 7.87–7.89 (m, 1H), 7.90 (s, 1H), 7.93 (d, J=4.07 Hz, 2H), 7.96 (d, J=5.76 Hz, 1H); MS (ESI(+)) m/e 425 (M+H)+
Reaction SMILES: [CH2:1]([N:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH2:17]Cl.C(O)(C)C>O>[Cl-:14].[CH2:10]([N+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:17][C:16]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:15]=1[Cl:14])[CH2:11][CH2:12][CH3:13]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: CCCCN(CCCC)CCCC
Solvent: O
Solvent: CC(C)O
Product: CCCC[N+](CCCC)(CCCC)Cc1ccc(Cl)cc1Cl
Product: [Cl-]
Yield: 67 %

Procedure:
One hundred eighty-five and four-tenths parts of tributylamine and 97.8 parts of 2,4-dichlorobenzyl chloride were mixed with 78.5 parts of isopropanol and placed in a reactor equipped with a stirrer, condenser and thermometer. The mixture was heated for 6 hours with stirring at 80° C. after which the isopropanol and excess tributylamine were removed by distillation at 2 mm. and 80° C. 124.2 parts of crude product were obtained. The crude product was dissolved in 300 parts of water, and the water solution was washed with about 50 parts of hexane. The hexane was separated from the water and the water was removed by distillation, giving a recovery from the wash step of 67% tributyl-2,4-dichlorobenzylammonium chloride. Refractive index at 24° C., 1.529; Ionic Cl (Calc.) 9.31%; Cl (found) 9.34% (Volhard).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[N:7]=1.C(N(CCCC)CCCC)CCC.[CH3:29][N:30]([CH3:46])[C:31](=[O:45])[C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:33]=1[S:41]([NH2:44])(=[O:43])=[O:42].[OH-].[K+]>C(OCC)(=O)C.O>[CH3:29][N:30]([CH3:46])[C:31](=[O:45])[C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:33]=1[S:41]([NH:44][C:1]([NH:5][C:6]1[N:7]=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([O:12][CH3:13])[N:11]=1)=[O:2])(=[O:42])=[O:43]
Reactant: COc1cc(OC)nc(N)n1
Reactant: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Reactant: O=C(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOC(C)=O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cc([N+](=O)[O-])ccc2C(=O)N(C)C)n1
Temperature: 30 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
Phosgene (23 g, 232 mmol) was passed into ethyl acetate (250 ml) at 10° C. A solution of 2-amino-4,6-dimethoxypyrimidine (20 g, 129 mmol) and tributylamine (47.82 g, 258 mmol) in ethyl acetate (270 ml) was added dropwise in the course of 3 h. 15 min after the addition, the jacket was warmed to 30° C. and ethyl acetate and excess phosgene were distilled off in vac. The remaining solution of the isocyanate was cooled to 10° C. and added dropwise to a suspension of N,N-dimethyl-2-aminosulfonyl-4-nitro-benzamide (31.7 g, 116 mmol) and tributylamine (22.96 g, 232 mmol) in ethyl acetate (100 ml) at 20° C. in the course of 3 h. The mixture was stirred for 1 h and treated with water (300 ml) and potassium hydroxide solution (10% strength, 240 ml). After phase separation, the organic phase was extracted with water (50 ml). The combined aqueous phases were extracted with ethyl acetate (50 ml) and adjusted to pH 2 to 3 using 6M hydrochloric acid. After filtering off the product, washing with water (2×100 ml) and drying, 49.09 g (85.8% of theory) of N,N-dimethyl-2{-N-[N-(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl}-4-nitrobenz-amide were obtained.
Reaction SMILES: [H-].[Na+].C([O:7][C:8](=[O:18])[CH2:9][CH:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11](O)=O)(C)(C)C.O>C1COCC1>[CH2:14]([CH:10]1[CH2:11][O:18][C:8](=[O:7])[CH2:9]1)[CH:15]([CH3:16])[CH3:17]
Reactant: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC1COC(=O)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 104.9 %

Procedure:
Triethyl phosphonoacetate (1.13 mL, 5.70 mmol) was added dropwise to a stirring suspension of sodium hydride (0.22 g of a 60% dispersion in oil, 5.43 mmol) in THF (15 mL) at 0° C. under argon. After 20 minutes, ketone 3 (0.75 g, 5.43 mmol) in THF (6 mL) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 16 hours. Water (5 mL) was added, and the mixture was extracted with ether (15 mL×3). The combined organic fractions were washed with brine and dried (MgSO4). The solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane/ethyl acetate, 95:5) to give the ester 4 (0.81 g, 72%) as a colorless oil; Rf(heptane/ethyl acetate, 8:2) 0.66; νmax(film)/cm−1 1715 (C═O), 1652 (C═C); δH (400 MHz; CDCl3): 5.80 (1H, quint, J=2.2, CHCO2Et), 4.15 (2H, q, J=7.1, CO2CH2Me), 2.79 (1H, dd, J=19.5, 8.1), 2.69 (1H, ddt, J=19.8, 7.3, 2.3), 2.47 (1H, dd, J=17.3, 7.2), 2.34 (1H, ddt, J=17.3, 5.6, 1.8), 2.14 (1H, m), 2.02 (1H, m), 1.60–1.22 (8H, m); m/z (ES+) 209 (M+H, 57%), 455 (2M+K, 67).
Reaction SMILES: [N:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[C:4](=[O:10])[CH2:3][CH2:2]2.[BH4-].[Na+].O>CO>[N:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH:4]([OH:10])[CH2:3][CH2:2]2
Reactant: O=C1CCN2CCCC1C2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC1CCN2CCCC1C2
Temperature: -10 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
1-Aza-bicyclo[3.3.1]nonan-4-one (11.92 g, 85.6 mmol) is dissolved in 160 ml MeOH and cooled to −10° C. NaBH4 (1.69 g, 42.9 mmol)) is added portionwise so that the inner temperature does not exceed 0° C. The reaction mixture is stirred at −10° C. for 1 h. Water is added and the solvents are evaporated. The remaining solid is dissolved in MTBE/MeOH, filtered over hyflo and the filtrate is evaporated to give 19.28 g of crude product which is purified by chromatography over aluminum oxide (400 g, eluent: MTBE/MeOH 95:5 to 80:20) to give 10.96 g (91%) (4SR,5RS)-1-aza-bicyclo[3.3.1]nonan-4-ol.
Reaction SMILES: [CH2:1]([O:3][C:4](/[C:6](=[C:11](\[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)/[CH2:7][C:8](O)=[O:9])=[O:5])[CH3:2].CO>O1CCCC1>[Cl:28][C:25]1[CH:24]=[CH:23][C:22](/[C:11](/[C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=2)=[C:6](/[CH2:7][CH2:8][OH:9])\[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:27][CH:26]=1
Reactant: CCOC(=O)/C(CC(=O)O)=C(\c1ccc(Cl)cc1)c1ccc(S(C)(=O)=O)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)/C(CCO)=C(\c1ccc(Cl)cc1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of 32.8 g (0.0775 mole) of (Z)-3-ethoxycarbonyl-4-(4-chlorophenyl)-4-(4-methanesulfonylphenyl)but-3-enoic acid, prepared in example 3, in 90 ml of anhydrous tetrahydrofuran are added dropwise 15.5 ml (0.155 mole) of borane/dimethyl sulfide complex. The mixture is stirred at room temperature for 8 hours and 23.5 ml of methanol are added dropwise. The mixture is evaporated to dryness in vacuo and the residue is dissolved in ethyl acetate. After washing with potassium carbonate solution, the organic phase is separated, dried over magnesium sulfate and evaporated in vacuo to give 30.8 g of ethyl (Z)-3-(4-chlorophenyl)-3-(4-methanesulfonylphenyl)-2-(2-hydroxyethyl)prop-2-enoate as crystals with a melting point of 128° C. after recrystallization from isopropanol.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl-:9].[CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][P+:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)c1ccc(CCl)cc1
Product: CC(C)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Cl-]

Procedure:
reacting para-isopropylbenzyl chloride with triphenylphosphine in the presence of a suitable solvent at a temperature of and for a sufficient period of time to form a slurry of para-isopropylbenzyl triphenylphosphonium cloride in the solvent,
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][OH:15]>O>[Cl:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:15][CH3:14])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=C(Cl)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CO
Solvent: O
Product: COC(=O)c1ccc(S(=O)(=O)Cl)cc1

Procedure:
4-Chlorosulfonylbenzoyl chloride (2), (83.27 mMole) was cooled in an ice/acetone bath while methanol (50 mL) was slowly added with good stirring and mixing, keeping the temperature below 20° C. After the addition, the mixture was stirred at room temperature for 15 minutes and then treated with water (100 mL). The white solid was filtered off, washed well with water and air-dried to give 19 g of methyl 4-chlorosulfonylbenzoate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[CH3:17][N:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[N:19]1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][N:18]1[C:22]([C:2]2[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=2)=[CH:21][CH:20]=[N:19]1
Reactant: COC(=O)c1cc(Br)cs1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)cs1
Temperature: 75 °C
Yield: 70.1 %

Procedure:
To a solution of methyl 4-bromo-2-thiophenecarboxylate (1.0 g, 4.5 mmol) in dioxane/H2O (5:1, 12 mL) was added K2CO3 (1.86 mg, 13.5 mmol), tetrakistriphenylphosphine Pd(0) (300 mg, 0.25 mmol), and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.23 g, 5.9 mmol). The reaction mixture was heated to 75° C. in a sealed tube for 2 h. The reaction mixture was concentrated and purified on silica gel (EtOAc/Hex 10-40%) to give the title compound (701 mg, 70%) as a white solid: LC-MS (ES) m/z 223 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[CH:6]2.B(Br)(Br)Br.O.C(Cl)(Cl)Cl>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[CH:6]2
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc2cc(O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a -65° C. solution of 8.6 g (53.4 m mol) 5-methoxy-2-methyl indole in 110 mL of CH2Cl2 was added dropwise 30.4 g (117 m mol) of boron tribromide. The reaction was allowed to warm to room temperature and stirred for 30 minutes. After cooling the mixture to 5° C., 200 mL of 50% water/chloroform was cautiously added. The aqueous layer was separated and the pH adjusted to 5.8 with aqueous sodium hydroxide. Extracting the mixture twice with 100 mL of ethyl acetate, followed by drying (Na2SO4), filtering and concentrating provided 5.3 g of the product as a yellow solid, mp 124°-126° C. 1H NMR (60 MHz, 20% DMSO d6 /CDCl3) δ 8.05 (s, 1H, NH), 7.05 (d, J=8 Hz, 1H), 6.80 (d, J=2 Hz, 1H), 6.55 (dd, J=2, 8 Hz, 1H), 5.90 (broad s, 1H, indole CH), 2.40 (s, 3H).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:35][CH:36]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:37][NH:38][C:39]([CH:41]1[CH2:46][CH:45]([CH3:47])[CH2:44][CH2:43][CH:42]1[CH:48]([CH3:50])[CH3:49])=[O:40]>O.C(OCC)(=O)C.C1COCC1>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]([C:11](=[O:13])[NH:35][CH:36]([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[CH2:37][NH:38][C:39]([CH:41]1[CH2:46][CH:45]([CH3:47])[CH2:44][CH2:43][CH:42]1[CH:48]([CH3:50])[CH3:49])=[O:40])[CH3:10])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC1CCC(C(C)C)C(C(=O)NCC(N)c2ccccc2)C1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1CCC(C(C)C)C(C(=O)NCC(NC(=O)C(C)NC(=O)OC(C)(C)C)c2ccccc2)C1
Reaction time: 3 h
Yield: 25.5 %

Procedure:
A 15 mL reaction vessel equipped with a stir bar was charged with THF (15 mL), Boc-(R)-alanine (52 mg, 0.273 mmoles), HOBt (37.87 mg, 0.273 mmoles), EDCI (53 mg, 0.273 mmoles) and TEA (37 μl, 0.273 mmoles). The reaction mixture was stirred for 15 min. whereupon 2-isopropyl-5-methyl-cyclohexanecarboxylic acid (2-amino-2-phenyl-ethyl)-amide (75 mg, 0.248 mmol) was added and stirred for an additional 3 h. Ethyl acetate (10 mL) and H2O (10 mL) were added to the reaction mixture. The heterogeneous mixture was transferred to a separatory funnel where the aqueous phase was separated and re-extracted with ethyl acetate (2×10 mL). The organic phases were combined and washed with 1N HCl (2×10 mL), H2O (1×10 mL), sat NaHCO3 (3×10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (20% ethyl acetate/hexane for elution) provided the title compounds as colorless solid (30 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([CH2:12]Br)[CH:3]=1.[NH3:14].CO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:7])[NH:14][CH2:12]2
Reactant: N
Reactant: COC(=O)c1ccc(Br)cc1CBr
Solvent: CO
Solvent: C1CCOC1
Product: O=C1NCc2cc(Br)ccc21
Reaction time: 24 h
Yield: 52 %

Procedure:
A solution of Example 33B (1.1 g, 3.57 mmol) in THF (20 mL) at room temperature was treated with 1N NH3 in methanol (7.14 mL, 7.14 mmol), stirred for 24 hours, and filtered. The filter cake was washed with diethyl ether (100 mL) to provide the desired product (0.4 g, 52%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[N:11]([O-])=O.[Na+]>O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][NH2:11])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(NN)cc1
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
To a mixture of 100 g of 4-aminobenzonitrile, 500 ml of water and 360 g of concentrated hydrochloric acid, a liquid mixture of 60.2 g of sodium nitrite and 240 ml of water was added at 0° C., and the resulting mixture was stirred for 30 minutes. The mixture was added to a liquid mixture of 382 g of stannous chloride dihydrate and 480 g of concentrated hydrochloric acid at 15° C., and the resulting crystals were collected by filtration, washed with water and then suspended in 1,000 ml of water. 300 ml of 5N aqueous sodium hydroxide was added to the suspension, and the resulting mixture was stirred for 1.5 hours. The resulting crude product was washed with water and recrystallized in benzene to give 70.2 g of the title compound as pale brown crystals.