Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl.[CH2:33]([N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][C@@H:41]1[CH2:46]Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:46][CH:41]3[CH2:42][CH2:43][CH2:44][CH2:45][N:40]3[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:27])([F:28])[F:29])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Reactant: BrC[C@H]1CCCCN1Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CC2CCCCN2Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a solution of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (4.5 g, 0.011 mol, 1.0 eq) in DMSO (100 mL) and add powdered KOH (3.0 g, 0.055 mol, 5.0 eq) at RT under nitrogen atmosphere and stir for 30 minutes. To the resulting solution add (R)-1-benzyl-2-(bromomethyl)piperidine hydrochloride (5.0 g, 0.0165 mol, 1.5 eq) and stir the reaction mass at RT for 16 h. After completion, dilute the reaction with water (100 mL) and extract the compound in EA (3×100 mL). Wash the organic layer with brine (2×50 mL) and dry over anhydrous sodium sulfate. Concentrate the organic layer under reduced pressure and purify on silica (100-200 mesh) using 2% acetone-DCM to get 3.0 g (46%) of the title compound. (ES+): m/z=601 (M+H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:8]([CH3:16])=[C:9]([C:13]([NH2:15])=[O:14])[NH:10][C:11]=1[CH3:12])=O.[N+]([O-])(O)=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH2:32])=[NH:31])=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>COCCO>[F:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]2[N:32]=[C:5]([C:7]3[C:8]([CH3:16])=[C:9]([C:13]([NH2:15])=[O:14])[NH:10][C:11]=3[CH3:12])[CH:4]=[CH:3][N:31]=2)=[CH:27][CH:28]=1
Reactant: Cc1[nH]c(C(N)=O)c(C)c1C(=O)C=CN(C)C
Reactant: N=C(N)Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCO
Solvent: O=[N+]([O-])O
Product: Cc1[nH]c(C(N)=O)c(C)c1-c1ccnc(Nc2ccc(F)cc2)n1
Temperature: 120 °C
Yield: 22.2 %

Procedure:
4-(3-Dimethylamino-acryloyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid amide (100 mg, 0.43 mmol), 4-fluorophenylguanidine nitrate (139 mg, 0.65 mmol) and K2CO3 (94 mg, 0.68 mmol) were partially dissolved in 2-methoxyethanol (5 mL) and heated at 120° C. for 18 h. The mixture was concentrated in vacuo and purified by SiO2 chromatography (EtOAc/MeOH gradient elution). The crude product was triturated in iPr2O to afford the title compound (31 mg) as a buff solid. M.p. 93.5–96.8° C. MS: [M+H+]=326.9 (C17H16FN5O requires 325.3). 1H-NMR (DMSO-d6) δ: 2.36 (s, 3H, CH3), 2.39 (s, 3H, CH3), 6.79 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 6.92 (br. s, 2H, NH), 7.07 (t, 2H, J=8.5 Hz, Ph-H), 7.76–7.78 (m, 2H, Ph-H), 8.36 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 9.41 (s, 1H, NH), 11.24 (br. s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([N+:13]([O-])=O)=[C:6]([NH:8][CH2:9][C:10](O)=[O:11])[CH:7]=1.O.O.[Sn](Cl)Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[CH3:16])[NH:13][C:10](=[O:11])[CH2:9][NH:8]2
Reactant: Cc1cc([N+](=O)[O-])c(NCC(=O)O)cc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Cc1cc2c(cc1Cl)NCC(=O)N2
Temperature: 25 °C
Yield: 31.2 %

Procedure:
A solution of N-(5'-chloro-4'-methyl-2'-nitrophenyl)glycine (1.000 g, 4.088 mmol, as prepared above) and tin (II) chloride dihydrate (2.767 g, 12.26 mmol, Aldrich, used as received) in ethanol (20.0 mL) was refluxed for 30 min. It was then cooled to room temperature and the precipitated solid was filtered, washed with ethanol (4.0 mL), and dried under vacuum to yield 0.251 g (31%) of the title compound as a yellow powder; 1H NMR (DMSO-d6): δ2.093 (s, 3H), 3.657 (d, 2H, J=1.5 Hz), 5.984 (s, 1H), 6.583 (s, 1H), 6.632 (s, 1H), 10.253 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([CH:6]3[CH:11]([CH:12]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[CH2:13]2)[CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:4][C:3]=1[O:24][CH3:25].C[Li].[Li][C:29](C)(C)C.CI>>[CH3:25][O:24][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:2]=1[CH3:29])[CH2:13][CH:12]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: [Li]C(C)(C)C
Reactant: COc1ccc(C2Cc3cc(Br)c(OC)cc3C3CCCCC23)cc1
Agent: [Li]C
Solvent: CI
Product: COc1ccc(C2Cc3cc(C)c(OC)cc3C3CCCCC23)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
At −78° C., combine 7-Bromo-6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthrene (chiral) (0.027 g, 0.067 mmol), and CH3Li (0.09 ml, 1.6M), then add t-BuLi (0.1 ml, 1.7M). After 30 minutes add CH3I (0.04 ml, 0.61 mmol) and remove cooling. After 1 hour at r.t., add ammonium chloride solution solution and ethyl acetate. Wash organic layer with water, dry over anhydrous sodium sulfate, remove solvent in vacuo to yield the titled compound (0.026 g, 100%). 1H NMR (CDCl3):): 7.27 (d, J=8.8 Hz, 2H), 6.99 (s, 1H), 6.93 (d, J=8.8 HZ, 2H), 6.89 (s, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.2 (m, 2H), 2.85 (dd, J=4 and 11, 1H), 2.48 (d, J=14 Hz, 1H), 2.06 (m, 1H), 1.8-0.8 (m, 8H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH:13]1([CH2:12][O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCC2CC2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
4-Nitrophenol (5.0 g, 35.9 mmol) was added to a suspension of (bromomethyl)cyclopropane (10.7 g, 79.07 mmol) and K2CO3 (19.9 g, 143.76 mmol) in DMF (80 mL), and the reaction was stirred at 40° C. overnight. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (100 mL×3). Organics were washed with brine (50 mL), dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography (0-5% EtOAc/PE) to give 6.77 g (98%) of the title compound as a colorless oil. [M+H] Calc'd for C10H11NO3, 194. Found, 194.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:14]([CH3:25])[N:15]=[C:16]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:33]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)[C:34]([NH2:36])=[O:35].O>CN(C)C=O>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([C:16]2[C:5]3[C:4]4[CH:3]=[C:2]([O:1][CH:33]([C:37]5[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=5)[C:34]([NH2:36])=[O:35])[C:11]([O:12][CH3:13])=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:14]([CH3:25])[N:15]=2)=[CH:18][CH:19]=1)#[N:22]
Reactant: NC(=O)C(Br)c1ccc(F)cc1
Reactant: COc1cc2ncc3c(c(-c4ccc(C#N)cc4)nn3C)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncc3c(c(-c4ccc(C#N)cc4)nn3C)c2cc1OC(C(N)=O)c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 18 h
Yield: 47.6 %

Procedure:
4-(8-Hydroxy-7-methoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-1-yl)benzonitrile (97.7 mg, 296 μmol) is dissolved in N,N-dimethylformamide (3.7 ml). Potassium carbonate (102 mg, 738 μmol) and 2-bromo-2-(4-fluorophenyl)acetamide (170 mg, 733 μmol) are subsequently added. The reaction mixture is stirred at 120° C. for 18 h. When the reaction is complete, the mixture is poured into water (50 ml) and extracted three times with ethyl acetate (50 ml each time). The combined organic phases are dried over Na2SO4, filtered with suction and evaporated in vacuo. The residue is then suspended in a little 2-propanol, filtered off with suction and dried in a high vacuum, giving 2-[1-(4-cyanophenyl)-7-methoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yloxy]-2-(4-fluorophenyl)acetamide (68 mg, 141 μmol) as a solid having a melting point of 249.2° C. MS: 482.1 (M+H+), TLC (HPTLC): Rf=0.31 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: [ClH:1].[CH2:2]([C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1)[CH2:3][CH2:4][C:5]#[CH:6].[N:13]([CH2:16][C:17]([CH3:25])=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N+:14]=[N-:15]>>[ClH:1].[CH3:25][C:17](=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][N:13]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:7]2[NH:8][C:9]([NH2:12])=[N:10][CH:11]=2)[N:15]=[N:14]1
Reactant: CC(=Cc1ccccc1)CN=[N+]=[N-]
Reactant: C#CCCCc1c[nH]c(N)n1
Agent: Cl
Product: CC(=Cc1ccccc1)Cn1cc(CCCc2cnc(N)[nH]2)nn1
Yield: 41 %

Procedure:
4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.096 g, 0.517 mmol) was reacted with (3-Azido-2-methyl-propenyl)-benzene (0.110 g, 0.635 mmol) following the general procedure for click reactions outlined above to produce 5-{3-[1-(2-Methyl-3-phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-propyl}-1H-imidazol-2-ylamine hydrochloride (0.076, 41%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.65 (s, 1H), δ 7.14-7.04 (m, 5H), δ 6.35 (s, 1H), δ 6.28 (s, 1H), δ 4.94 (s, 2H), δ 2.57 (t, 2H), δ 2.34 (t, 2H), δ 1.75 (m, 2H), δ 1.57 (s, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 147.5, 136.9, 132.5, 129.7, 128.8, 128.6, 128.4, 128.3, 128.2, 126.9, 122.5, 109.2, 58.1, 61.9, 28.0, 24.3, 24.3, 24.1, 14.6 ppm; HRMS (ESI) calcd for C18H22N6 (M+) 323.1978. found 323.1984.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([NH:15][C@@H:16]([C:22](=[O:24])[NH2:23])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC2N=NN(OS(C3C=CC(Cl)=CC=3)(=O)=O)C=2C=1.[CH2:46](O)[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([NH:15][C@@H:16]([C:22](=[O:24])[NH2:23])[CH2:17][CH2:18][C:19]([O:21][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH3:46])=[O:20])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCC(=O)O)C(N)=O
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: O=S(=O)(On1nnc2ccc(Cl)cc21)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOC(=O)CC[C@@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(N)=O
Yield: 36.8 %

Procedure:
t-Butyloxycarbonyl-L-valyl-D-isoglutamine (1.73 g, 5 mmol) and 6-chloro-1-p-chlorobenzenesulfonyloxybenzotriazole (2.06 g, 6 mmol) were reacted in DMF (5 ml) in the presence of TEA (0.84 ml) in a similar manner to that in Example 6 (II). Then stearyl alcohol (4.05 g, 15 mmol) and TEA (0.7 ml) were added and the mixture was reacted at room temperature for 20 hours. The usual work-up as described in Example 6 (II) gave stearyl t-butyloxycarbonyl-L-valyl-D-isoglutaminate (1.10 g). m.p. 88°-89° C. [α]D23 +4.0° (C 0.5, DMF). Rf2 =0.68, Rf3 =0.34
Reaction SMILES: [F:1][C:2](=[C:11]([F:13])[F:12])[CH2:3][CH2:4][S:5][C:6]1[O:7][CH:8]=[CH:9][N:10]=1.CN(C=O)C.S(Cl)([Cl:22])(=O)=O>C(Cl)(Cl)Cl>[Cl:22][C:8]1[O:7][C:6]([S:5][CH2:4][CH2:3][C:2]([F:1])=[C:11]([F:12])[F:13])=[N:10][CH:9]=1
Reactant: FC(F)=C(F)CCSc1ncco1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: FC(F)=C(F)CCSc1ncc(Cl)o1
Temperature: 50 °C
Reaction time: 3 h
Yield: 51.5 %

Procedure:
4.0 g of 2-(3,4,4-trifluoro-3-butenylthio)oxazole was added to 40 ml of DMF (dehydrated) to which a mixture of 10 ml of chloroform and 2.6 g of sulfuryl chloride was added dropwise at 50 in 1 hour. After the reaction mixture was stirred at 50° C. for 3 hours, a mixture of 5 ml of chloroform and 0.8 g of sulfuryl chloride was further added dropwise in 15 minutes. After stirring at 50° C. for 15 hours, the reaction mixture was cooled to room temperature, poured into 200 ml of ice water and extracted with 100 ml of hexane. The aqueous layer was neutralized with 1N aqueous solution of sodium hydroxide and further extracted with 100 ml of hexane. The extracted hexane layers were put together, washed with 200 ml of saturated common salt water and dried with magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (eluent: hexane:dichloromethane=1:1) to obtain 2.4 g of 5-chloro-2-(3,4,4-trifluoro-3-butenylthio)oxazole as colorless oil (yield 51.5%, n20D=1.4830).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][O:11][CH2:12][C:13](O)=[O:14].CN([P+](ON1N=NC2C1=CC=CC=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:13](=[O:14])[CH2:12][O:11][CH3:10])=[N:6][CH:7]=1
Reactant: NCc1ccc(Br)cn1
Reactant: COCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)NCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A mixture of (5-bromopyridin-2-yl)methanamine (358 mg, 1.914 mmol), 2-methoxyacetic acid (0.191 mL, 2.488 mmol), BOP-reagent (1101 mg, 2.488 mmol) and diisopropylethylamine (1.003 mL, 5.74 mmol) in DMF (8 mL) was stirred at rt for 2 hr. The reaction mixture was partitioned between EtOAc (60 ml) and saturated NaHCO3 solution (60 ml). The organic layer was washed with 10% LiCl solution (2×50 ml) and brine (50 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to afford an orange oil that was chromatographed on a 24 gm ISCO silica gel cartridge, eluting with a 0-100% EtOAc/Hex gradient. The pure fractions were concentrated to afford N-((5-bromopyridin-2-yl)methyl)-2-methoxyacetamide (337 mg, 1.301 mmol, 68.0% yield) as an orange oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.62 (d, J=2.2 Hz, 1H), 7.79 (dd, J=8.4, 2.4 Hz, 1H), 7.44 (d, J=4.8 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 4.56 (d, J=5.5 Hz, 2H), 3.97 (s, 2H), 3.45 (s, 3H). MS (ES+) m/z: 259.0, 261.0 (M+H); LC retention time: 0.907 min (analytical HPLC Method O).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[N+:9]([O-])([OH:11])=[O:10].[OH-].[Na+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(Br)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
100 ml of concentrated sulfuric acid were added to 25.0 g of 2-amino-5-bromopyridine, and 8.9 ml of concentrated nitric acid were then added dropwise to the mixture at a temperature of 50° to 60° C. over a period of 1 hour. The mixture was then stirred at 60° C. for 30 minutes. At the end of this time, the reaction mixture was poured into ice-water and neutralized by the addition of an aqueous solution of sodium hydroxide. The crystals which precipitated were collected by filtration and washed with ethanol, to give 19.1 g of the title compound, melting at 180°-182° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][N:26]1[C:30]([S:31](Cl)(=[O:33])=[O:32])=[CH:29][N:28]=[C:27]1[CH3:35].C(N(CC)CC)C>>[CH3:25][N:26]1[C:30]([S:31]([N:22]2[CH2:23][CH2:24][CH:19]([C:10]3[C:9]4[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=4)[NH:12][CH:11]=3)[CH2:20][CH2:21]2)(=[O:33])=[O:32])=[CH:29][N:28]=[C:27]1[CH3:35]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Reactant: Cc1ncc(S(=O)(=O)Cl)n1C
Solvent: CCN(CC)CC
Product: Cc1ncc(S(=O)(=O)N2CCC(c3c[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)n1C

Procedure:
Following the general procedure in example 267, 5-(phenyl)-3-(4-piperidinyl)-1H-indole-7-carboxamide (72 mg, 0.22 mmol), 1,2-dimethyl-1H-imidazole-5-sulfonyl chloride (64.2 mg, 0.33 mmol) and triethylamine (0.13 mL, 0.66 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (48.3 mg, 45%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][N:6]=[C:7]=[O:8])=[O:4].[CH2:9]([O:11][C:12]([NH:14][NH2:15])=[O:13])[CH3:10]>C1(C)C=CC=CC=1>[CH2:9]([O:11][C:12]([NH:14][NH:15][C:7]([NH:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[O:8])=[O:13])[CH3:10]
Reactant: COC(=O)CN=C=O
Reactant: CCOC(=O)NN
Solvent: Cc1ccccc1
Product: CCOC(=O)NNC(=O)NCC(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
A solution of 19.72 g (0.17 mol) of methoxycarbonylmethyl isocyanate in 70 ml of dry toluene was added dropwise at room temperature to a stirred solution of 18.00 g (0.17 mol) of ethoxycarbonylhydrazine in 400 ml of dry toluene. The mixture was stirred at room temperature overnight and filtered. The colourless solid was washed with toluene, dried and recrystallized from ethyl acetate to give 28.54 g (76%) of 1-ethoxycarbonyl-4-methoxycarbonylmethyl-semicarbazide of melting point 116°-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=O)[CH2:7][CH:8]2[C:13](=O)[CH2:12][CH2:11][S:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH2:21][CH2:22][NH2:23])[CH3:20].C(O)(=O)C.Cl>O>[CH3:18][N:19]([CH3:20])[CH2:21][CH2:22][N:23]1[C:6]([C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:7][C:8]2[CH2:9][S:10][CH2:11][CH2:12][C:13]1=2
Reactant: CN(C)CCN
Reactant: O=C(CC1CSCCC1=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CN(C)CCn1c(-c2ccc(Cl)cc2)cc2c1CCSC2

Procedure:
A solution of 5.0 g (0.019 mole) of 3-(4-chlorophenacyl)-2,3,5,6-tetrahydrothiopyran-4-one, 7.14 g of dimethylaminoethylamine and 15 ml. of acetic acid is heated under reflux under nitrogen for 24 hours, diluted with water, acidified with hydrochloric acid, extracted with ether, neutralized with sodium hydroxide, and extracted with chloroform. The chloroform solution is dried over magnesium sulfate and concentrated. The residue is recrystallized from ethanol to give off-white crystals of 1-(2-dimethylaminoethyl)-2(4-chlorophenyl)-1,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrole, m.p. 91.5° to 92.5°C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:12]([NH:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(COC)OC.O>[C:2]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:12]([NH:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(Nc2nc(C)ccc2S(=O)(=O)c2ccc(Br)cc2)c(C)c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C)c(Nc2nc(C)ccc2S(=O)(=O)c2ccc(-c3ccccc3)cc2)c(C)c1
Yield: 47 %

Procedure:
[3-(4-Bromobenzenesulfonyl)-6-methylpyridin-2-yl]-(2,4,6-trimethylphenyl)-amine, prepared as described in Example 46, (100 mg, 0.225 mmol), phenylboronic acid (32.9 mg, 0.269 mmol), Pd(PPh3)2Cl2 (7.7 mg, 0.011 mmol) and Ba(OH)2.8H2O (84.6 mg, 0.269 mmol) were heated at reflux in 1:1 dimethoxyethane/water (2 mL) for 20 h. The reaction was partitioned between EtOAc (100 mL) and water (20 mL) and the organic extract was washed with brine, dried, and stripped in vacuo. The residue was purified by silica gel chromatography (10% EtOAc/hexanes eluent) to give the title compound as a solid (47 mg, 47% yield), mp 140–141° C. mass spec. (AP+): m/z 443 (M+1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[N:8](C)[CH:9]=[O:10].[O:12]=[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:14][CH2:15][CH2:16][CH2:17]C(O)=O>O1CCCC1>[O:12]=[C:13]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:14][CH2:15][CH2:16][CH2:17][C:9]([NH2:8])=[O:10]
Reactant: O=C(O)CCCCC(=O)c1ccccc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)CCCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
Oxalyl chloride (0.508 ml) and N,N-dimethylformamide (catalytic amount) were added to a solution of 6-oxo-6-phenylhexanoic acid (1.00 g) in tetrahydrofuran (15 ml) at room temperature, which was stirred at room temperature for 1 hour and concentrated. The residue was dissolved in ethyl acetate (25 ml) and added dropwise to a stirred mixture of 25% aqueous ammonia (20 ml) and ethyl acetate (25 ml) at 0° C. After stirring at room temperature for 2 hours, water (200 ml) was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 6-oxo-6-phenylhexanamide (885 mg, yield 89%) as colorless crystals. m.p. 113-114° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1F)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[CH3:21][O:22][CH2:23][C@@H:24]([NH2:26])[CH3:25]>>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[NH:26][C@@H:24]([CH3:25])[CH2:23][O:22][CH3:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1F
Reactant: COC[C@H](C)N
Agent: O=C([O-])O
Agent: [Na+]
Product: COC[C@H](C)Nc1cc(F)ccc1C(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
A mixture of 2,4-difluoro-benzoic acid tert-butyl ester (30 g, 140.05 mmol) and (S)-2-methoxy-1-methyl-ethylamine (100 mL) was stirred at 65° C. for 2 days. A satured solution of NaHCO3 was added and the mixture was extracted with dichloromethane (3×). The organic phase was washed with water (2×), brine, dried over sodium sulfate filtered and evaporated to dryness to obtain a crude, which was purified by column chromatography on silica gel (exane-EtOAc 9:1). The title compound (33.38 g, 84%) was obtained as oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:13]([OH:15])=O)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[NH2:21][C:22]1[C:23]([CH3:37])=[C:24]([CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:25]=[CH:26][CH:27]=1>CN(C=O)C.N1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:13]([NH:21][C:22]2[C:23]([CH3:37])=[C:24]([CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH:25]=[CH:26][CH:27]=2)=[O:15])=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: Cc1c(N)cccc1CCC(=O)OC(C)(C)C
Reactant: CC(=O)OCc1ccc(C(C(=O)O)C2CCCC2)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)OCc1ccc(C(C(=O)Nc2cccc(CCC(=O)OC(C)(C)C)c2C)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.41 g (90% pure, 37.16 mmol) of (+/−)-{4-[(acetyloxy)methyl]phenyl}(cyclopentyl)acetic acid were dissolved in a mixture of 71.8 ml of DMF and 22.5 ml of pyridine, and 15.54 g (40.88 mmol) of 1-[bis(dimethylamino)methylene]-5-chloro-3-oxy-1H-benzotriazol-1-ium tetrafluoroborate and 8.75 g (37.16 mmol) of tert-butyl 3-(3-amino-2-methylphenyl)propanoate were added. The reaction mixture was stirred at RT overnight and then concentrated under high vacuum. The residue was taken up in 100 ml of ethyl acetate and washed successively with 10% strength aqueous citric acid, saturated sodium bisulfate solution and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1→3:1). This gave 16.36 g (89.2% of theory) of the title compound.