Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:29][CH:30]([CH2:34][OH:35])[C:31](O)=[O:32])(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:29][CH:30]([CH2:34][O:35][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[C:31]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17][CH:18]=2)=[O:32])(=[O:27])=[O:28])=[CH:24][CH:25]=1
Reactant: O=C(O)C(CO)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: C1=COCCC1
Product: CCOC(=O)c1ccc(NC(=O)C(COC2CCCCO2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 35.8 %

Procedure:
The procedure described in Example 1 was repeated, except that dihydropyran (2.7 g) and ethyl p-aminobenzoate (2.13 g) were successively reacted with (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid (3 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide (1.962 g).
Reaction SMILES: [S:1](=[O:4])(=O)=[O:2].N1C=CC=CC=1C.[Cl:12][C:13](=[CH2:19])[CH2:14][NH:15][CH2:16][CH2:17][CH3:18].P(Cl)(Cl)([Cl:22])=O>ClCCCl.C(OC)(C)(C)C>[Cl:12][C:13](=[CH2:19])[CH2:14][N:15]([CH2:16][CH2:17][CH3:18])[S:1]([Cl:22])(=[O:4])=[O:2]
Reactant: C=C(Cl)CNCCC
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)=O
Solvent: ClCCCl
Solvent: COC(C)(C)C
Solvent: Cc1ccccn1
Product: C=C(Cl)CN(CCC)S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
35.7 g (0.256 mol) of sulfur trioxide as a 57.4% solution in 1,2-dichloroethane were added with stirring at from 0 to 5° C. within 15 min to a solution of 43.7 g (0.469 mol) of α-picoline in 200 ml of 1,2-dichloroethane, followed by washing with 40 ml of 1,2-dichloroethane and stirring for 15 min-until the temperature rose to 20° C. 28.5 g (0.192 mol) of 90% pure N-(2-chloro-2-propen-1-yl)-N-propylamine were then added within 15 min with stirring and external cooling at from 20 to 30° C., followed by washing with 40 ml of 1,2-dichloroethane and stirring at 50° C. for 15 min. After cooling to 23° C., 39.3 g (0.256 mol) of phosphorus oxychloride were added with stirring within 15 min, followed by washing with 120 ml of 1,2-dichloroethane and heating to 70° C. After stirring for 1 h, the reaction mixture was cooled and concentrated under reduced pressure, and the residue obtained was stirred with 100 ml of methyl tert-butyl ether each time. The methyl tert-butyl ether phases were decanted off and concentrated. The residue was distilled. 42.5 g (90.5% of theory) of the title compound having a boiling point of 67-71° C./0.4 mbar were obtained.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:5])=[O:4].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CN(C=O)C>[CH3:1][N:2]([CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[S:3]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:5])=[O:4]
Reactant: ClCCN1CCOCC1
Reactant: CNS(=O)(=O)c1ccsc1C(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sccc1S(=O)(=O)N(C)CCN1CCOCC1
Reaction time: 5 h

Procedure:
To a solution of methyl 3-(N-methylsulfamoyl)thiophene-2-carboxylate (prepared in an analogous manner as described in Example 10, Scheme 10, Step 1, 530 mg, 2.253 mmol) in dry DMF (20 ml) under nitrogen atmosphere, K2CO3 (623 mg, 4.51 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (838 mg, 4.51 mmol) were added, and the mixture was reacted at 60° C. overnight and then at 80° C. for 5 hours. The insoluble inorganic salts were filtered off, the filtrate was evaporated and the residue was purified by flash chromatography on silica gel (DCM/MeOH=9/1) to afford methyl 3-(N-methyl-N-(2-morpholinoethyl)sulfamoyl)thiophene-2-carboxylate (Int. 47) (510 mg, 1.464 mmol, MS/ESI+348.8 [MH]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:15][C:14](=[O:16])[CH:13]([CH3:17])[CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[C:24]([O:26][CH:27]([F:29])[F:28])[CH:23]=[CH:22][N:21]=1>>[F:29][CH:27]([F:28])[O:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([CH2:19][N:15]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH:13]([CH3:17])[C:14]2=[O:16])[CH:25]=1
Reactant: FC(F)Oc1ccnc(CBr)c1
Reactant: COc1cccc(OC)c1C1CC(C)C(=O)N1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cc(OC(F)F)ccn1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 5-(2,6-dimethoxyphenyl)-3-methylpyrrolidin-2-one with 2-(bromomethyl)-4-(difluoromethoxy)pyridine. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.67 min.; [M+H]+: 393.08 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[CH3:18][C:19]1([CH3:26])[O:23][C@H:22]([CH2:24]O)[CH2:21][O:20]1.Cl[CH2:28]Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:28][C@@:22]1([CH3:24])[CH2:21][O:20][C:19]([CH3:18])([CH3:26])[O:23]1)=[O:15])[CH:7]=[CH:6]2
Reactant: ClCCl
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: CC1(C)OC[C@@H](CO)O1
Product: COc1ccc2cc([C@H](C)C(=O)OC[C@@]3(C)COC(C)(C)O3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 33.5 g, 0.145 mol) and ((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)methan-1-ol (15 g, 0.113 mol) in anhydrous dichloromethane (750 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbamide hydrochloride (EDAC, 23 g, 0.12 mol) and N,N-dimethylaminopyridine (DMAP, 7.5 g, 61 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight, then quenched with water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and solvent evaporated under reduced temperature. The product was purified by column chromatography on silica gel eluting with EtOAc:hexane (2:8) to give the title compound (35.8 g, 92% yield) as a white solid. Mp 79-80° C. 1H NMR (CDCl3) δ 7.76 (d, J=9.1 Hz, 2H), 7.46 (dd, J=8.7, 1.8 Hz, 1H), 7.19 (m, 2H), 7.0 (s, 1H), 4.28 (m, 1H), 4.18 (m, 2H), 4.0 (m, 2H), 3.94 (s, 3H), 3.68 (m, 1H), 1.65 (d, J=7.1 Hz, 3H), 1.41 (s, 3H), 1.38 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 174.4, 157.6, 135.3, 133.7, 129.2, 128.9, 127.1, 126.1, 126.0, 119.0, 109.6, 105.5, 73.4, 66.1, 64.4, 55.2, 45.2, 26.5, 25.3, 18.4; LRMS (APIMS) m/z 345 (MH)+.
Reaction SMILES: C([O:3][CH:4]=[CH2:5])=C.[CH:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH:4](=[O:5])[CH:3]=[CH:10][CH2:11][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C=COC=C
Reactant: c1ccccc1
Product: CCCCCC=CC=O

Procedure:
The above vinyl ether was dissolved in benzene (100 ml.) and the solution was refluxed for 120 hours under Argon. The solvent was removed at reduced pressure to give a yellow oil (~ 1.289 g.). This was chromatographed on 25 g. of silica gel and elution with 1:9 parts by volume of ether:petroleum ether (b.p. 30°-60°) gave 792 mg. of material. This was further purified by Kugelrohr distillation at 36°/0.5 mmHg to yield 3(S),7-dimethyl-4trans)octenal as a colorless oil, [α] D25 + 30.18° (c= 3.572, CHCl3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[O:16].O[Li].O>C1COCC1.N1C=CC=CC=1>[C:8]1([C:4]2[CH:3]=[C:2]([NH:1][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:16])[CH:7]=[CH:6][CH:5]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)CCCCCCC(=O)Cl
Reactant: Nc1cccc(-c2ccccc2)c1
Agent: [Li]O
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(O)CCCCCCC(=O)Nc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-amino-biphenyl (315, 536 mg, 3.17 mmol) in THF/pyridine (2:1, 6 mL) was added methyl 7-(chlorocarbonyl)heptanoate (0.49 mL, 3.48 mmol), and the resulting solution was stirred at room temperature for 16 h. After dilution with saturated NaCl solution (15 mL) and extraction with ethyl acetate, the organic layer was dried over Na2SO4, filtered and concentrated. The residue was then dissolved in THF/methanol/H2O (1:1:2, 8 mL), followed by the treatment of LiOH—H2O (665 mg, 15.85 mmol). The reaction mixture was stirred at room temperature for 1 h prior to acidification (pH=1), and extraction with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated. After purification by flash chromatography (eluent 0-100% EtOAc in hexanes), the title compound 316 was obtained as a white solid (889 mg, 86% yield). 1H NMR: (DMSO) δ (ppm): 1.30-1.40 (m, 4H), 1.50-1.59 (m, 2H), 1.60-1.68 (m, 2H), 2.24 (t, J=7.4 Hz, 2H), 2.37 (t, J=7.4 Hz, 2H), 7.32 (dt, J=7.8, 1.6 Hz, 1H), 7.36-7.42 (m, 2H), 7.46-7.52 (m, 2H), 7.58-7.64 (m, 3H), 7.96 (s, 1H), 10.07 (br s, 1H). MS: (calc.) 325.4; (obt.) 326.1 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[C@H:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH2:21]=O>C(O)=O>[Cl:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[C@H:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][N:8]([CH3:21])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: C=O
Reactant: COc1cc2c(cc1Cl)CCNC[C@H]2c1ccccc1
Solvent: O=CO
Product: COc1cc2c(cc1Cl)CCN(C)C[C@H]2c1ccccc1

Procedure:
Reflux for 4 hours, a solution of 52.0 g (0.18 moles) of the product of step C in a mixture of 96 ml of 37% formaldehyde and 144 ml of 90% formic acid. Distill almost to dryness at 100° C. under reduced pressure (about 100 mm). Dissolve the residue in a mixture of 500 ml of 1 N sodium hydroxide and 500 ml of ethyl ether with cooling and stirring. Separate the ether layer, dry over anhydrous sodium sulfate, and evaporate to give (S)-7-chloro-8-methoxy-3-methyl-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepine as a colorless solid. Obtain an analytically pure sample by crystallization from ethyl ether, m.p. 91°-92° C., [α]D26 =+47.3°(c=1, ethanol).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][O:7][C@H:6]1[N:19]=[N+]=[N-])(=[O:3])[CH3:2].[H][H].[C:24](OCC)(=[O:26])[CH3:25]>[Pd]>[C:24]([NH:19][C@@H:6]1[O:7][CH2:8][C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]1[O:4][C:1](=[O:3])[CH3:2])(=[O:26])[CH3:25]
Reactant: CCOC(C)=O
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1N=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd]
Product: CC(=O)N[C@@H]1OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 16 h

Procedure:
In 20 ml of ethyl acetate was dissolved 0.73 g of 2,3,4-tri-O-acetyl-1-azido-1-deoxy-β-D-xylopyranose, and 65 mg of 10% Pd/C was added to the solution. Then the solution was stirred in a hydrogen atmosphere for 2 hours. The Pd/C was removed by filtration, and the filtrate was concentrated. To the concentrate was added 20 ml of pyridine, 3 ml of acetic anhydride and then 10 mg of 4-dimethylaminopyridine, and the mixture was stirred for 16 hours. Water was added to the reaction, and the mixture was extracted with chloroform. The chloroform layer was washed with 0.1 N HCl solution, 1% sodium bicarbonate solution and finally with water, dehydrated and concentrated. The residue was subjected to silica gel column chromatography with a system of chloroform-acetone (100:1) to obtain 0.4 mg of 1-acetamido-2,3,4-tri-O-acetyl-1-deoxy-β-D-xylopyranose.
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([NH:8][C:9](=[O:27])[NH:10][C:11]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]([C:15]([OH:17])=O)=[CH:13][N:12]=1)[CH3:7].N1C(C)=CC=CC=1C.[F:36][C:37]([F:46])([F:45])[C:38]1[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=1[NH2:40]>CC(N(C)C)=O>[CH2:6]([NH:8][C:9](=[O:27])[NH:10][C:11]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]([C:15]([NH:40][C:39]2[CH:41]=[CH:42][CH:43]=[CH:44][C:38]=2[C:37]([F:36])([F:45])[F:46])=[O:17])=[CH:13][N:12]=1)[CH3:7]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)O)cn1
Agent: CS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: Cc1cccc(C)n1
Product: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)Nc2ccccc2C(F)(F)F)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 7 %

Procedure:
An ice-cold solution of methane sulfonyl chloride (18 μL, 0.23 mmol) in DMA (2.0 mL) was stirred for 10 min followed by sequential drop wise addition of a solution of 6-(3-ethylureido)-4-(phenylamino)nicotinic acid (50 mg, 0.16 mmol) in DMA (5.0 mL) and 2,6-lutidine (55 μL, 0.46 mmol). The resulting reaction mixture was stirred at 0° C. for 30 min followed by addition of a solution of 2-trifluoromethyl aniline (31 μL, 0.25 mmol) in DMA (1.0 mL). The reaction mass was further stirred at RT ° C. for 10 min and then heated at 50° C. for 4 h. The reaction mass was then cooled to 0-5° C. and quenched with H2O (5.0 mL), followed by addition of conc. HCl (0.50 mL). The resulting solution was stirred for 5 min followed by extraction with EtOAc (3×50 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified via preparative TLC to obtain Compound 11 (5.0 mg, 8%). 1H NMR (300 MHz, DMSO-d6): δ 10.23 (br s, 1H), 10.07 (br s, 1H), 9.12 (br s, 1H), 8.61 (s, 1H), 7.89 (m, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.74 (m, 1H), 7.57 (m, 2H), 7.38-7.43 (m, 2H), 7.31 (s, 1H), 7.25 (m, 2H), 7.15 (m, 1H), 3.14 (m, 2H) and 1.06 (t, J=7.20 Hz, 3H). [M+H]+ m/z=444.17.
Reaction SMILES: C([Li])(C)(C)C.CCCCC.Br[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][C:13]=1[CH3:20].[B:21](OC)([O:24]C)[O:22]C>C(OCC)C>[CH3:20][C:13]1[CH:14]=[C:15]([S:18][CH3:19])[CH:16]=[CH:17][C:12]=1[B:21]([OH:24])[OH:22]
Reactant: CSc1ccc(Br)c(C)c1
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CSc1ccc(B(O)O)c(C)c1
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 50 %

Procedure:
1.7M tert-Butyllithium in pentane (6.70 mL, 11.39 mmol) was added dropwise to a solution of 1-bromo-2-methyl-4-(methylthio)benzene (1.2 g, 5.53 mmol) in diethyl ether (120 mL) at −78° C. over 15 min. The mixture was stirred at −78° C. for 2 min, then charged with trimethyl borate (0.661 mL, 5.91 mmol) dropwise over 2 min at −78° C., stirred at −78° C. for 15 min, then brought to ambient temperature. The mixture was quenched with saturated aqueous NH4Cl (14 mL), stirred at ambient temperature for 15 min, charged with 1M HCl (12 mL), stirred at ambient temperature for 2 min, and the organics were separated. The organics were dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 20 to 100% EtOAc/hexane to give 503 mg (50%) of [2-methyl-4-(methylthio)phenyl]boronic acid as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.79 (d, 1H, J=7.8 Hz), 7.09-7.00 (m, 2H), 2.61 (s, 3H), 2.46 (s, 3H); LRMS (ESI), m/z 183 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]4[NH2:24])[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl[C:46]([O:48][CH3:49])=[O:47]>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]4[NH:24][C:46](=[O:47])[O:48][CH3:49])[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCC[C@@H]4N)n3)c3cc(Cl)cnc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)N[C@H]1CCCC[C@@H]1Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(Cl)cc23)ncc1F
Reaction time: 0.58 h

Procedure:
To a mixture of (1S,2S)—N1-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)cyclohexane-1,2-diamine, 23b, (0.18 g, 0.35 mmol) in dichloromethane (4 mL) at room temperature was added iPr2NEt (0.12 mL, 0.70 mmol) followed by methyl chloroformate (0.03 mL, 0.37 mmol). After 35 minutes. the mixture was diluted with EtOAc, washed successively with aqueous saturated NH4Cl and aqueous saturated NaHCO3 and brine, dried over Na2SO4 filtered and concentrated in vacuo to provide the crude product sufficiently pure for use in the next reaction.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[N:27]1([C:33]([C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[N:27]1([C:33]([C:35]2[CH:42]=[CH:41][C:38]([C:39]3[NH:10][C:9]4[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:26])[C:15]5[CH:20]=[CH:19][C:18]([N:21]6[CH2:25][CH2:24][CH2:23][CH2:22]6)=[CH:17][CH:16]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:37][CH:36]=2)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: O=Cc1ccc(C(=O)N2CCOCC2)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCCC2)cc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(C(=O)N4CCOCC4)cc3)nc2c1)c1ccc(N2CCCC2)cc1

Procedure:
Compound 239 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-pyrrolidinylbenzamide and 4-morpholinylcarbonylbenzaldehyde. [M+H]+ calcd for C29H29N5O3: 496.24; found: 496.25.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23](O)=[O:24])=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN(C=O)C.[Cl:53][C:54]1[CH:60]=[CH:59][C:57]([NH2:58])=[CH:56][CH:55]=1>C1COCC1>[Cl:53][C:54]1[CH:60]=[CH:59][C:57]([NH:58][C:23]([C:15]2[C:16]3[O:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]=3[C:11]3[NH:10][C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:13][C:12]=3[CH:14]=2)=[O:24])=[CH:56][CH:55]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4ccccc4Cl)[nH]c23)O1
Reactant: Nc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(Cl)cc3)cc3nc(Nc4ccccc4Cl)[nH]c23)O1
Yield: 23.1 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(2-chlorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-12, 0.050 g, 0.139 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.089 g, 0.277 mmol), TEA (1.0 mL), DMF (1.0 mL), THF (5.0 mL) and 4-chloro aniline (0.035 g, 0275 mmol) to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 1.60 (s, 6H), 3.17 (s, 2H), 7.05 (t, J=7.5 Hz, 1H), 7.36-7.43 (m, 2H), 7.49 (d, J=7.8 Hz, 2H), 7.75 (d, J=8.1 Hz, 2H), 8.58-8.60 (m, 1H), 9.07 (s, 1H), 9.87 (s, 1H), 11.02 (s, 1H), 11.36 (s, 1H); MS [M+H]+: 467.23.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17]CC[C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][N:22]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[N:23]1.N1C=C(B(O)O)C=NC=1>>[N:13]1([C@H:11]2[CH2:10][C@H:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:25]5[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=5)[CH:20]=[CH:19][C:5]=4[N:6]=3)[CH2:12]2)[CH2:14][CH2:18][CH2:17]1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: OB(O)c1cncnc1
Product: Cn1cc(-c2ccc3nc([C@H]4C[C@H](N5CCC5)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, except for substituting the product of Example 61A for the product of Example 1E, and substituting 1-methyl-1H-pyrazoleboronic acid pinacol ester for pyrimidine-5-boronic acid. 1H NMR (300 MHz, CDCl3) δ ppm 7.89-7.97 (m, 2H) 7.80 (s, 1H) 7.65 (s, 1H) 7.55 (dd, J=8.31, 1.86 Hz, 1H) 3.97 (s, 3H) 3.92-4.07 (m, 1H) 3.21-3.45 (m, 5H) 2.36-2.62 (m, 4H) 2.06-2.24 (m, 2H). MS: (M+H)+=325.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH2:41])=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54].Cl>ClCCl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH:41][S:53]([CH3:52])(=[O:55])=[O:54])=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCNS(C)(=O)=O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole (0.36 g) in dichloromethane (6 mL) were added triethylamine (0.2 mL) and methanesulfonyl chloride (0.05 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/3-ethyl acetate) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonylamino)-propoxy]phenyl}methyl)-1H-pyrazole (255 mg). This material was dissolved in methanol (6 mL). To the solution was added sodium methoxide (28% methanol solution, 0.11 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (0.16 g).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]#N.[CH3:8][N:9]([CH:11]=O)C.[ClH:13].O.C[N:16]([CH:18]=O)C>Cl>[Cl:13][C:8]1[CH:5]=[CH:4][C:3]([C:18]#[N:16])=[CH:11][N:9]=1
Reactant: Cl
Reactant: CN(C)C=O
Reactant: CN(C)C=CC#N
Solvent: O
Product: N#Cc1ccc(Cl)nc1
Temperature: 50 °C

Procedure:
13.2 g of β-dimethylamino-acrylonitrile were added dropwise at 30° C. to a solution of 22 g of DMF/HCl adduct in 100 ml of DMF. Following an after-reaction time of 2 h, this solution was added dropwise, while passing in HCl, to a solution, saturated at 50° C., of HCl gas in DMF. The temperature was maintained at 50° C. by cooling. After conventional work up (40 ml of water), 2-chloro-5-cyanopyridine was obtained in 77.7% of the theoretical yield, based on the C3 unit employed.