Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[NH:12][C:11]=2[CH3:23])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[OH-].[Na+]>C(OCC)C.C(Cl)(Cl)Cl>[C:31]([NH:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[NH:12][C:11]=2[CH3:23])[CH2:4][CH2:3]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1cc2[nH]c(C)c(CCN3CCN(N)CC3)c2cc1OC
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1cc2[nH]c(C)c(CCN3CCN(NC(=O)c4ccccc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred mixture of 7.92 g (0.025 mol) of 3-[2-(4-aminopiperazin-1-yl)ethyl]-5,6-dimethoxy-2-methylindole and 3.54 g (0.035 mol) of triethylamine in 75 ml. of chloroform is cooled to -5° C., with the exclusion of moisture. Then a solution of 4.20 g (0.03 mol) of benzoyl chloride in 6 ml. of chloroform is added dropwise over a 30 minute span, while maintaining a temperature of 0°-5° C. After total addition, the mixture is stirred at ambient temperature for two hours. Then 50 ml. of 10% sodium hydroxide is added, followed by 50 ml. of ethyl ether to promote crystallization. After stirring for 15minutes, another 100 ml. of ethyl ether is added to improve crystallization form. The product is filtered, washed well with water, then ethyl ether and dried. This crystalline product is recrystallized twice from DMF and water mixture to give pure needles of 3-[2-(4 -benzamidopiperazin-1-yl)ethyl]-5,6-dimethoxy-2-methylindole, m.p. 128°-131° C. Analysis: Calculated for C24H30N4O3 : 68.22% C; 7.16% H; 13.26% N Found: 68.03% C; 7.14% H; 13.12% N.
Reaction SMILES: CC(O)=[O:3].O.[F:6][C:7]([F:13])([F:12])[CH2:8][C:9](=[O:11])[CH3:10]>O1CCOCC1>[F:6][C:7]([F:13])([F:12])[CH2:8][C:9](=[O:11])[CH:10]=[O:3]
Reactant: CC(=O)O
Reactant: CC(=O)CC(F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: O=CC(=O)CC(F)(F)F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of SeO2 (4.23 g, 38.1 mmol) in dioxane (25 mL) was added AcOH/H2O (1 mL/1 mL). 4,4,4-Trifluorobutan-2-one (3.81 mL, 31.7 mmol) was added dropwise to the above reaction mixture. The resulting solution was stirred overnight at 100° C. The solution was used in the next step without any further work-up or purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([CH2:40][CH2:41][C:42](=[NH:45])[NH:43][OH:44])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:46][CH3:47])=[O:5])[CH3:2].C1N=CN([C:53](N2C=NC=C2)=[O:54])C=1>C(#N)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=3)[C:22]([CH2:40][CH2:41][C:42]3[NH:45][C:53](=[O:54])[O:44][N:43]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:46][CH3:47])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CCC(=N)NO)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CCc3noc(=O)[nH]3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 60 °C
Reaction time: 25.5 h
Yield: 57.8 %

Procedure:
(2R,4S)-4-([3,5-Bis(trifluoromethyl)benzyl]-{5-[2-(N-hydroxy-carbamimidoyl)ethyl]pyrimidin-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (140 mg) is dissolved in acetonitrile (1 ml), and thereto is added carbodiimidazole (51 mg). The mixture is heated at 60° C. and stirred for 25.5 hours. The reaction solution is cooled to room temperature, and partitioned by adding water and ethyl acetate. The organic layer is washed with saturated brine, then dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=1:0→19:1) to give (2R,4S)-4-([3,5-bis-(trifluoromethyl)benzyl]-{5-[2-(5-oxo-4,5-dihydro[1,2,4]oxadiazol-3-yl)ethyl]pyrimidin-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (84 mg). MS (m/z): 696 [M+H]+.
Reaction SMILES: ClC1C=CC(C[N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15](=[O:31])[CH2:16][NH:17][C:18](=[O:30])[C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=3[NH2:29])[CH2:9][CH2:8]2)=CC=1>C(O)=O.CO.[OH-].[OH-].[Pd+2]>[NH2:29][C:20]1[CH:21]=[CH:22][C:23]([C:25]([F:28])([F:26])[F:27])=[CH:24][C:19]=1[C:18]([NH:17][CH2:16][C:15]([NH:14][CH2:13][CH:10]1[CH2:9][CH2:8][NH:7][CH2:12][CH2:11]1)=[O:31])=[O:30]
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Solvent: CO
Product: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)NCC1CCNCC1
Temperature: 50 °C
Reaction time: 14 h
Yield: 85.2 %

Procedure:
A suspension of 1-(4-chlorobenzyl)-4-[{(N-(2-amino-5-trifluoromethylbenzoyl)glycyl)amino}methyl]piperidine (447 mg, 0.93 mmol) and Pd(OH)2 (60 mg, 0.23 mmol) in 5% HCO2H/methanol (10 mL) was stirred at 50° C. for 14 h. The Pd catalyst was filtered off through Celite, and the filtrate was concentrated. To the residue was added 1 N aqueous NaOH solution (15 mL) and the mixture was extracted with ethyl acetate (30 mL×3). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO2, AcOEt/MeOH/Et3N=70/25/5) gave 4-[{(N-(2-amino-5-trifluoromethylbenzoyl)glycyl)amino}methyl ]piperidine (284 mg, 86%): ESI/MS m/e 359.0 (M++H, Cl16H21F3N4O2).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][O:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[N:37]=[C:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH:35]=[CH:34]2>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:42]2[CH2:43][CH2:44][N:39]([C:36]3[CH:35]=[CH:34][C:33]4[C:38](=[C:29]([O:28][CH3:27])[CH:30]=[CH:31][CH:32]=4)[N:37]=3)[CH2:40][CH2:41]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: COc1cccc2ccc(N3CCNCC3)nc12
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: COc1cccc2ccc(N3CCN(CCCCC4(C(=O)NCC(F)(F)F)c5ccccc5-c5ccccc54)CC3)nc12

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 8-methoxy-2-piperazin-1-yl-quinoline.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][C@H:4]([NH2:17])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH2:33][C:34](O)=[O:35])[CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:20]>>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH2:33][C:34]([NH:17][CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:3][CH:2]([CH3:18])[CH3:1])=[O:35])[CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:20]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: CC(C)C[C@H](N)c1ccccc1N1CCCCC1
Product: CCOC(=O)c1ccc(CC(=O)NC(CC(C)C)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
Prepared from (S)-3-Methyl-1-(2-piperidino-phenyl)-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid analogously to Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:6]([O:7][CH2:8][CH3:9])[O:5][C:4](=[O:10])[CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23](O)=[O:24])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>ClCCl.C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[C:23](=[O:24])[NH:1][C:2]1[CH:6]([O:7][CH2:8][CH3:9])[O:5][C:4](=[O:10])[CH:3]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC1OC(=O)C=C1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC1OC(=O)C=C1NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 72 h
Yield: 8.8 %

Procedure:
A solution of 4-amino-5-ethoxy-5H-furan-2-one (0.04 g, 0.30 mmol), (S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (0.07 g, 0.30 mmol), diisopropylethylamine (0.12 mL, 0.66 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (0.14 g, 0.38 mmol) in dichloromethane (3 mL) was stirred 24 h, was evaporated, was redissolved in 1-methyl-pyrrolidinone (3 mL) and was stirred 3 d. The reaction was diluted with ethyl acetate, was washed with 10% sodium bisulfate, saturated sodium bicarbonate, and brine, was dried over sodium sulfate, and was evaporated. Purification by two flash chromatographies (SiO2), eluted first with 4:6, then with 35:65 ethyl acetate:hexanes afforded (R )-2-(2-ethoxy-5-oxo-2,5-dihydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.009 g, 9% yield) as a film. 1H-NMR (500 MHz, CDCl3) δ 10.2 (br s, 0.7H), 10.1 (br s, 0.3H), 6.21 (br s, 0.7H), 6.17 (br s, 0.3H), 5.68 (s, 0.7H), 5.60 (br s, 0.3H), 4.38 (br s, 1H), 3.85 (m, 1H), 3.72 (m, 1H), 3.25-3.45 (m, 2H), 2.53 (br d, 12.5 Hz, 0.7H), 2.1 (br, 0.3H), 1.87 (br m, 3H), 1.44 (s, 9H), 1.21 (m, 3H) ppm. MS (ES+): m/e=341 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[N:41][CH:42]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC#N.O>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([C:37]5[CH:42]=[N:41][C:40]([N:43]6[CH2:44][CH2:45][O:46][CH2:47][CH2:48]6)=[CH:39][CH:38]=5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(N5CCOCC5)nc4)ccc2OCC3)c(F)c1
Temperature: 80 °C
Yield: 1.8 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (4.16 mg, 10 mmol), 4-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-morpholine (350 mg, 12 mmol), Cs2CO3 (650 mg, 2.0 mmol), Pd(dppf)Cl2 (73 mg, 0.10 mmol) and CH3CN—H2O (1:1, 4 mL) were added in a 50 mL of sealed tube, and the mixture was heated by microwave at 80° C. for 60 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (50 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative TLC to give 248 (98.1 mg, yield: 18%). 1HNMR (DMSO-d6, 400 MHz): δ8.75 (s, 1H), 8.28 (s, 1H), 8.06 (d, J=2.4 Hz, 1H), 7.73-7.71 (m, 1H), 7.45-7.41 (m, 2H), 7.41-7.38 (m, 2H), 7.14 (s, 1H), 6.93 (d, J=8.8 Hz, 1H), 4.27 (s, 2H), 3.74 (s, 4H), 3.53 (s, 4H), 3.11 (s, 2H). ESI-MS: m/z=545 [M+H+]
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:35]([O:37][CH3:38])=[O:36]>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCCc2ccccc2)c1
Reactant: COC(=O)Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CCc2ccccc2)C(=O)OC)c1

Procedure:
Prepared according to the procedure described in Example 23, Step 1, using the following starting materials: [6-methoxy-2′-(phenethylamino-methyl)-4-'-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester and methyl chloroformate.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:23])=[C:4]([CH3:22])[C:5]2[O:9][C:8](=[O:10])[C:7]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)([CH3:11])[C:6]=2[CH:21]=1>C(OCC)(=O)C.CCCCCC>[Br:1][C:2]1[CH:21]=[C:6]([C:7]([C:12]2[CH:13]=[CH:14][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=2)([CH3:11])[CH2:8][OH:10])[C:5]([OH:9])=[C:4]([CH3:22])[C:3]=1[CH3:23]
Reactant: Cc1c(Br)cc2c(c1C)OC(=O)C2(C)c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(Br)cc(C(C)(CO)c2ccc(C(C)C)cc2)c(O)c1C
Yield: 83 %

Procedure:
Using 5-bromo-3-(4-isopropylphenyl)-3,6,7-trimethyl-1-benzofuran-2(3H)-one synthesized in Reference Example 21, the title compound was synthesized in the same manner as in Reference Example 8. Yield 83%. Melting point: 110-111° C. (ethyl acetate-hexane).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)=[N:6][CH:7]=1.[OH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[C:8]([C:5]2[N:4]=[CH:3][C:2]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:26][OH:25])=[CH:7][N:6]=2)=[N:9]1
Reactant: OCc1ccccc1B(O)O
Reactant: Fc1ccccc1Cn1nc(-c2ncc(Br)cn2)c2cccnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: OCc1ccccc1-c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1

Procedure:
200 mg (0.52 mmol) of 3-(5-bromo-2-pyrimidinyl)-1-(2-fluorobenzyl)-1H-pyrazolo-[3,4-b]pyridine (example I, step 6), 90 mg (0.62 mmol) of 2-(hydroxymethyl)-phenylboronic acid, 40 mg (0.05 mmol) of 1,1′-bis(diphenylphosphino)-ferrocenepalladium(II) chloride and 200 mg (0.62 mmol) of cesium carbonate are taken up in 2 ml of DME and stirred under reflux overnight. The solvent is removed under vacuum, and the residue is purified by preparative HPLC to result in 111 mg (52% of theory) of the product.
Reaction SMILES: C([O:3][P:4]([C:7]1[CH:8]=[N:9][C:10]([NH:13][C:14](=[O:33])[C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH2:23][C:24]3[CH:28]=[CH:27][S:26][CH:25]=3)[CH:18]=[C:17]([O:29][CH:30]([CH3:32])[CH3:31])[CH:16]=2)=[CH:11][CH:12]=1)([CH3:6])=[O:5])C.C[Si](N[Si](C)(C)C)(C)C.C[Si](Br)(C)C.[Si](I)(C)(C)C>C(Cl)Cl>[CH:30]([O:29][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([O:21][CH2:22][CH2:23][C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)[CH:18]=1)[C:14]([NH:13][C:10]1[N:9]=[CH:8][C:7]([P:4]([CH3:6])(=[O:3])[OH:5])=[CH:12][CH:11]=1)=[O:33])([CH3:32])[CH3:31]
Reactant: CCOP(C)(=O)c1ccc(NC(=O)c2cc(OCCc3ccsc3)cc(OC(C)C)c2)nc1
Agent: C[Si](C)(C)Br
Agent: C[Si](C)(C)I
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: ClCCl
Product: CC(C)Oc1cc(OCCc2ccsc2)cc(C(=O)Nc2ccc(P(C)(=O)O)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
To a solution of {6-[3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoylamino]-pyridin-3-yl}-methyl-phosphinic acid ethyl ester (469 mg, 0.960 mmol) in DCM (10 mL) was added HMDS (1.62 mL, 7.68 mmol) and TMSBr (0.51 mL, 3.84 mmol) at rt. Stirred at rt overnight. TMSI (0.07 mL, 0.480 mmol) was added to the milky mixture on the second day. Stirred at rt for 1.5 hr. The mixture was concentrated, re-dissolved in EtOAc (10 mL), and filtered through a 0.4 μm syringe filter to remove insoluble NH4Br. The filtrate was concentrated and the residue was dissolved in MeOH (10 mL), stirred at rt for 3 hr, and concentrated again. The resulting residue was partitioned between EtOAc and water. After layers were separated, the aqueous layer was extracted with EtOAc (2×). Combined EtOAc layers were washed with brine (1×), dried with anhydrous MgSO4, filtered, and concentrated to give {6-[3-Isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoylamino]-pyridin-3-yl}-methylphosphinic acid (242 mg, 53%) as a yellow foam. 1H NMR (300 MHz, DMSO-d6): δ 11.08 (br, 1H), 8.68 (ddd, J=6, 2, 1 Hz, 1H), 8.32 (m, 1H), 8.14 (m, 1H), 7.51 (dd, J=5, 3 Hz, 1H), 7.36 (dd, J=3, 2 Hz, 1H), 7.24 (m, 1H), 7.20 (m, 1H), 7.15 (dd, J=5, 1 Hz, 1H), 6.71 (m, 1H), 4.77 (m, 1H), 4.28 (m, 2H). 3.11 (m, 2H), 1.58 (d, J=15 Hz, 3H), 1.30 (d, J=6 Hz, 6H); LC-MS (m/z): 461.3 [C23H25N2O5PS+H]+. Anal. Calcd. for (C23H25N2O5PS+1.1H2O): C, 55.02; H, 5.71; N, 5.83. Found: C, 55.02; H, 5.31; N, 5.44.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:22])([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:5][CH:4]=1.Br.[Br-].[K+].S([O-])([O-])=O.[Na+].[Na+].CBr>>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:22])([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[C:10]([CH3:13])([CH3:11])[CH3:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(P(=O)(c2ccc(OC)cc2)C(C)(C)C)cc1
Agent: Br
Agent: CBr
Agent: O=S([O-])[O-]
Product: CC(C)(C)P(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Yield: 42.1 %

Procedure:
Bis(4-methoxyphenyl)-tert-butylphosphine oxide mixture (25.0 g), hydrobromic acid (770 g, 48%), and potassium bromide (30.0 g) were stirred for 25 h at 120° C. The flask was fitted with a sodium sulfite scrubber for containment of methyl bromide. The reaction mixture was worked up to give a tan solid (9.6 g, 40%). 31P NMR (d6-DMSO): δ 46.3 (s, 31.8%), 39.6 (s, 31.7%), 28.7 (s, 20.4%), −8.2 (s, 16.1%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[S:6]([C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14]C)=[O:13])(=[O:8])=[O:7].[OH-].[Na+].Cl>CO>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[S:6]([C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:8])=[O:7]
Reactant: COC(=O)c1cccc(S(=O)(=O)c2nccs2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(S(=O)(=O)c2nccs2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a solution of methyl 3-(1,3-thiazol-2-ylsulfonyl)benzoate (82 mg) in methanol (1.5 mL) was added 1M aqueous sodium hydroxide solution (0.58 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was ice-cooled, 1M hydrochloric acid (1.0 mL) was added thereto, and the precipitate was collected by filtration to give the title compound (67 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:15](O)=[O:16]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:15]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:16]
Reactant: COc1ccc(N)cc1
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])c(OC)c2)cc1
Yield: 92.6 %

Procedure:
Using p-anisidine (738 mg, 6.0 mmol) and 3-methoxy-4-nitrobenzoic acid (986 mg, 5.0 mmol), the procedure of Reference Example 16 was repeated to obtain 1.40 g (92.7%) of the title compound in the form of colorless powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[H][H]>[Pt](=O)=O.C(O)(=O)C>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1ccncc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: O=C(O)CCC1CCNCC1

Procedure:
50 g (0.335 mol) of 3-(4-pyridyl)-acrylic acid are hydrogenated in 800 ml of 50% strength acetic acid with the addition of 10 g of platinum dioxide as the catalyst at room temperature under a hydrogen pressure of 50 psi until the uptake of hydrogen has ended. After the catalyst has been filtered off, the filtrate is concentrated to dryness in vacuo and the residue which remains is crystallized from a little methanol, after addition of ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[NH:19][CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([O:21][CH3:22])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4.[CH:23]1([CH2:26]Br)[CH2:25][CH2:24]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH:23]1([CH2:26][N:19]2[CH2:18][CH2:17][C@@:14]34[C:15]5[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[CH2:7][C@@H:8]2[C@:9]3([O:21][CH3:22])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4)[CH2:25][CH2:24]1
Reactant: BrCC1CC1
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@]1(OC)CCC(=O)C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)[C@]13CCN(CC4CC4)[C@H](C2)[C@]1(OC)CCC(=O)C3
Temperature: 110 °C

Procedure:
A mixture of 3,14-dimethoxymorphinan-6-one (6a) (4.491 g, 14.9 mmol), cyclopropylmethyl bromide (3.017 g, 22.35 mmol) and NaHCO3 (7.50 g, 89.4 mmol) in DMF (50 ml) was refluxed under nitrogen for 16 hours at 110° C. The mixture was filtered and the DMF removed by distillation under reduced pressure. The residue was taken up in methylene chloride (150 ml) and 150 ml of water. The two layers were separated and the aqueous layer re-extracted with methylene chloride (2×100 ml). The organic solutions were combined, washed with water (100 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting yellow solid was chromatographed on Florisil using graded methanol/chloroform as the eluant to give 17-cyclopropylmethyl-3,14-dimethoxymorphinan-6-one as a yellow oil which crystallized after drying the give 4.132 g (78% theory) of yellow solid. Recrystallization from ethanol gave 3.443 g (65%) of the title compound (8) (TR-5400) as colorless needles. A portion of 8 was converted to the hydrochloride salt (TR-5305) by treatment with ethereal hydrogen chloride to give a white solid, m.p. 215°-128° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH3:10])[NH2:9])[N:3]=1.O=[C:12]1[CH2:18][CH:17]2[N:19]([C:20]([O:22][CH:23]([Cl:25])[CH3:24])=[O:21])[CH:14]([CH2:15][CH2:16]2)[CH2:13]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:3]=[C:4]([N:8]([CH3:10])[N:9]=[C:12]2[CH2:13][CH:14]3[N:19]([C:20]([O:22][CH:23]([Cl:25])[CH3:24])=[O:21])[CH:17]([CH2:16][CH2:15]3)[CH2:18]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cl)OC(=O)N1C2CCC1CC(=O)C2
Reactant: CN(N)c1cccc(Br)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(Cl)OC(=O)N1C2CCC1CC(=NN(C)c1cccc(Br)n1)C2
Temperature: 25 °C
Yield: 20.6 %

Procedure:
A solution of 2-bromo-6-(1-methylhydrazinyl)pyridine (1.60 g, 7.90 mmol), 1-chloroethyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1.80 g, 7.90 mmol) and p-toluenesulphonic acid (300 mg, 1.60 mmol) in toluene (50 mL) was heated under reflux, with water removal (azeotrope), for 3 h. The mixture was cooled to room temperature and concentrated. The residue was purified by flash column chromatography (silica gel, 0%-100% solvent mixture B in methylene chloride; solvent mixture B=80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide) to give the title compound (676 mg, 28%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 7.31 (t, J=7.5 Hz, 1H), 6.88 (d, J=7.5 Hz, 1H), 6.68-6.65 (m, 1H), 6.62 (d, J=8.0 Hz, 1H), 4.63-4.40 (m, 3H), 3.17 (s, 3H), 2.93-2.90 (m, 1H), 265-2.62 (m, 1H), 2.42-2.37 (dd, J=16.0, 6.0 Hz, 1H), 2.13-2.00 (m, 3H), 1.85 (d, J=6.0 Hz, 3H), 1.80-1.73 (m, 1H).
Reaction SMILES: [O:1]=[C:2]([CH2:8][N:9]1[CH:12](SC)[CH2:11][C:10]1=[O:15])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Cl:16]Cl>C(Cl)(Cl)(Cl)Cl>[C:4](/[C:3](/[Cl:16])=[C:2]1\[CH2:8][N:9]2[CH:12]([O:1]\1)[CH2:11][C:10]2=[O:15])([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(=O)CN1C(=O)CC1SC
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C(Cl)=C1\CN2C(=O)CC2O1
Reaction time: 0.17 h
Yield: 119.3 %

Procedure:
Methyl 3-oxo-4-(2-oxo-4-methylthioazetidin-1-yl)butyrate (120 mg, 0.52 mmole) was dissolved in dry carbon tetrachloride (15 ml) and the solution was stirred and ice-cooled while chlorine (75 mg, 1.05 mmole) in carbon tetrachloride (1.4 ml) was added in one portion. The cooling bath was removed and stirring was continued for 10 minutes. The solvent was then evaporated under reduced pressure to yield a pale yellow gum (135 mg).