Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:4][N:5]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:2].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH2:1]([CH:3]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:4][N:5]1[C:6]2[CH:7]=[CH:8][C:9]([C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:29])=[CH:10][C:11]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:2]
Reactant: CCCCC(CC)Cn1c2ccccc2c2ccccc21
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC(CC)Cn1c2ccccc2c2cc(C(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15.6 %

Procedure:
To a solution of 9-(2-ethyl-hexyl)-9H-carbazole (7.0 g, 0.025 mol) in dichloromethane (30 ml), benzoyl chloride (4.5 g, 0.0525 mol) was added and stirred for 15 minutes at room temperature. Aluminium chloride (7.3 g, 0.055 mol) was added in portions while the temperature was maintained below 30° C. The reaction mixture was allowed to stir at room temperature for 15 hours. The reaction mixture was poured into ice (150 g) and distilled water (100 ml) and diluted with dichloromethane (200 ml). The organic layer was separated and washed with a saturated solution of sodium bicarbonate (250 ml) and a saturated solution of sodium chloride (250 ml). The organic layer was dried over MgSO4, filtered and the solvent was removed under reduced pressure. The residual solid was purified on a Prochrom LC80 Column using ethyl acetate/n-hexane (20/80) as eluent. TLC shows a yellow fluorescent product with Rf-value of 0.48 in dichloromethane as eluent. Evaporation of the pooled fractions yielded 1.5 g of [9-(2-ethyl-hexyl)-9H-carbazol-3-yl]-phenyl-methanone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C@@H:35]([CH2:44][OH:45])[C@@H:36]([OH:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C@@H:35]([CH2:44][OH:45])[C@@H:36]([OH:43])[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=S(=O)(N[C@@H](CO)[C@@H](O)c1ccccc1)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N[C@@H](CO)[C@@H](O)c3ccccc3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 2-bromo-N-((1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl)benzene-sulfonamide. MS (ESI): mass calcd. for C25H23FN4O4S, 494.14; m/z found, 495.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=1.4, 1H), 8.10 (s, 1H), 7.87-7.80 (m, 2H), 7.55 (t, J=7.5, 1H), 7.43-7.36 (m, 2H), 7.30-7.14 (m, 8H), 4.89 (d, J=4.0, 1H), 3.65-3.57 (m, 1H), 3.36 (d, J=1.4, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([NH:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[C:5]([Cl:8])=[CH:6][CH:7]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Product: CC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Yield: 98.5 %

Procedure:
A solution of 3-amino-6-chlorobenzotrifluoride (1.045 g, 5.34 mmol, Aldrich) in acetic anhydride (5 mL) was stirred at room temperature for 12 h to produce a white needle precipitate. It was filtered to give 1.250 g (98.5%) of 3-acetamido-6-chlorobenzotrifluoride. 1H NMR (CDCl3): δ2.193 (s, 3H); 7.420 (d, 1H, J=8.7 Hz); 7.726 (m, 2H), 7.804 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][N:35]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:36]=2)O1>>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][N:35]1[CH:36]=[C:32]([C:2]2[CH:23]=[CH:22][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:33]=[N:34]1)[CH3:42]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CCOC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCOC(=O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)cn1

Procedure:
Similarly to as described in General Procedure C, 8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 27 was reacted with ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate to give {4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-acetic acid ethyl ester as a colorless solid. LCMS: 466.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]1([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:17]([C@:11]1([C:14]([N:29]2[CH2:28][CH:27]=[C:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:31][CH2:30]2)=[O:16])[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)([CH3:19])[CH3:18]
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CC=C(c3ccccc3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
In a dried flask, (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (200 mg, 0.7 mmol) and 4-phenyl-1,2,3,6-tetrahydropyridine (160 mg, 0.81 mmol) were suspended in methylene chloride (4 mL) under N2. Triethylamine (0.22 g, 2.2 mmol) was added followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.36 g, 0.81 mmol). The reaction was stirred overnight at room temperature and quenched by addition of saturated NaHCO3 solution. The resulting solution was extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered and concentrated. Purification by flash chromatography on silica gel (gradient: 0-45% B over 15 min. Bottle A=hexanes, bottle B=EtOAc) to give 234 mg (80%) of desired product. MS calculated for C25H36N2O3: (M+H) 413; found 413.2.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([N:33]1[CH2:34][CH2:35][CH:30]([C:27]2[CH:26]=[CH:25][C:24]([CH3:23])=[CH:29][CH:28]=2)[CH2:31][CH2:32]1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C2CCNCC2)cc1
Reactant: O=C(O)c1cnc2c(Br)cnn2c1NCc1ccccc1
Agent: Cl
Product: Cc1ccc(C2CCN(C(=O)c3cnc4c(Br)cnn4c3NCc3ccccc3)CC2)cc1
Yield: 75.2 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.20 g, 0.58 mmol) obtained in Example 22, step 3 instead of 7-benzylamino-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid and 4-(4-methylphenyl)piperidine hydrochloride (0.15 g, 0.69 mmol), the title compound (0.22 g, 77%) was obtained.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N:10]([O-])=[O:11].[Na+].[Cl-].[K+]>C(O)(=O)C.O>[OH:11]/[N:10]=[C:2](/[C:3](=[O:4])[CH3:5])\[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(C)=O
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)/C(=N\O)C(C)=O
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a stirred and ice-cooled solution of ethyl acetoacetate (292 g) in glacial acetic acid (296 ml) was added a solution of sodium nitrite (180 g) in water (400 ml) at such a rate that the reaction temperature was maintained below 10° C. Stirring and cooling were continued for about 30 min., when a solution of potassium chloride (160 g) in water (800 ml) was added. The resulting mixture was stirred for one hour. The lower oily phase was separated and the aqueous phase was extracted with diethyl ether. The extract was combined with the oil, washed successively with water and saturated brine, dried, and evaporated. The residual oil, which solidified on standing, was washed with petrol and dried in vacuo over potassium hydroxide, giving ethyl (Z)-2-(hydroxyimino)-3-oxobutyrate (309 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.I[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[CH:23]([N:15]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([NH2:22])=[C:21]2[C:13]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:14]1)([CH3:25])[CH3:24]
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: COc1ccc(B(O)O)cc1
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: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COc1ccc(-c2nn(C(C)C)c3ncnc(N)c23)cc1
Temperature: 80 °C
Yield: 15.9 %

Procedure:
A solution of (4-Methoxyphenylboronic acid (17 mg, 0.11 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA48 (4.5 mg, 16% yield). ESI-MS (M+H)+ m/z calcd 284.1, found 284.1.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][CH2:14][C@@H:15]([NH:17]C(=O)OC(C)(C)C)[CH3:16])=[C:11]([C:27]([CH3:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])[CH:10]=1.[OH-].[Na+]>ClCCl>[Cl:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][CH2:14][C@@H:15]([NH2:17])[CH3:16])=[C:11]([C:27]([CH3:32])([CH3:33])[C:28]([F:29])([F:30])[F:31])[CH:10]=1
Reactant: C[C@@H](COc1ccc(Cl)cc1C(C)(C)C(F)(F)F)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)COc1ccc(Cl)cc1C(C)(C)C(F)(F)F
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl {(2S)-1-[4-chloro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]propan-2-yl}carbamate (C49) (600 mg, 1.52 mmol) in dichloromethane (24 mL), and the reaction mixture was stirred for 30 minutes. Aqueous sodium hydroxide solution (1 M, 50 mL) was added, and the mixture was extracted with diethyl ether (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the product as a light amber oil, which was used without further purification. Yield: 433 mg, 1.46 mmol, 96%. LCMS m/z 296.1, 298.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.24 (d, J=6.4 Hz, 3H), 1.67 (br s, 6H), 2.13 (br s, 2H), 3.41-3.50 (m, 1H), 3.79 (dd, half of ABX pattern, J=8.8, 7.2 Hz, 1H), 3.86 (dd, half of ABX pattern, J=8.9, 4.4 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 7.23 (dd, J=8.8, 2.5 Hz, 1H), 7.36-7.39 (m, 1H).
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(#N)C>[N+:9]([C:3]1[CH:4]=[C:5]([NH2:6])[CH:7]=[CH:8][C:2]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:11])=[O:10]
Reactant: C1CCNCC1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CC#N
Product: Nc1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
A solution of 1.00 g (6.41 mmol) of 4-fluoro-3-nitroaniline and 3.17 mL (32.1 mmol) of piperidine in 15 mL of acetonitrile under Ar was heated to reflux for 2 h. The mixture was cooled to RT, concentrated in vacuo, dissolved in EtOAc (60 mL) and washed with 1 M NaOH (2×50 mL), water (50 mL), brine (50 mL), and then dried (Na2SO4). Concentration afforded 1.40 g (99%) of the title compound as dark red crystals: 1H-NMR (CDCl3; 400 MHz): δ 7.04 (d, 1H, J=8.6 Hz), 7.03 (d, 1H, J=2.8 Hz), 6.81 (dd, 1H, J=8.6, 2.8 Hz), 2.85-2.88 (m, 4H), 1.65-1.70 (m, 4H), and 1.51-1.55 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].[OH-].[K+].[CH2:20](Br)[CH2:21][CH2:22][CH3:23]>CS(C)=O.O>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCBr
Reactant: Cc1ccccc1C(=O)Nc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCOc1cccc(NC(=O)c2ccccc2C)c1
Reaction time: 3 h
Yield: 92.9 %

Procedure:
A 22.7 g (0.1 mol) portion of 3'-hydroxy-2-methylbenzanilide was dissolved in 80 ml of dimethyl sulfoxide and to this solution was added a solution of 5.6 g (0.1 mol) of potassium hydroxide in 40 ml of water. The white mixture was cooled with water, and 30 ml of dimethyl sulfoxide containing 13.7 g (0.1 mol) of n-butylbromide was added dropwise to the solution with stirring. After the addition, the mixture was warmed and kept at 40° to 50° C for 3 hours. The reaction mixture was poured into 700 ml of water and the oily material formed was extracted with benzene. The benzene layer was washed with water, dehydrated over anhydrous sodium sulfate and the benzene was removed to obtain the product, which was recrystallized from a mixture of benzene and n-hexane (1 : 2) to obtain 26.3 g (92.9%) of greyish needle-like crystals having a melting point of 87° C.
Reaction SMILES: O[C:2]1([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:28][CH:27]=2)[C:7]2[CH:8]=[CH:9][C:10]([O:12]COC)=[CH:11][C:6]=2[O:5][CH2:4][CH:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22]COC)=[CH:18][CH:17]=1.[NH+]1C=CC=CC=1.O>CO>[OH:12][C:10]1[CH:9]=[CH:8][C:7]2[C:2]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]4[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]4)=[CH:28][CH:27]=3)=[C:3]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH2:4][O:5][C:6]=2[CH:11]=1
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(OCCN3CCCCC3)cc2)cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CO
Product: Oc1ccc(C2=C(c3ccc(OCCN4CCCCC4)cc3)c3ccc(O)cc3OC2)cc1
Temperature: 25 °C
Yield: 37 %

Procedure:
4-Hydroxy-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-4-[4-(piperidinoethyloxy)phenyl]-2,3-dihydro-4H-benzopyran (83 mg, 0.14 mmol) and pyridinium p-toulenesulfonate (214 mg, 1.4 mmol) were dissolved in methanol (6 ml) and then refluxed for 12 hours. The reaction solution was cooled to room temperature and, after adding water, extracted with ethyl acetate. The organic layer thus separated was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to remove the organic solvent. The residue was separated by column chromatography (n-hexane:ethyl acetate=1:4) to obtain 23 mg (yield: 37%) of the title compound as a foam.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:17][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: OCc1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=Cc1ccc(OCc2ccc(Cl)c(Cl)c2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.2 %

Procedure:
4-Hydroxy-3-nitrobenzaldehyde (448 mg, 2.68 mmol), 3,4-dichlorobenzyl alcohol (665 mg, 3.76 mmol), and triphenylphosphine (980 mg, 3.74 mmol) were dissolved in tetrahydrofuran (8 mL), and a diethyl azodicarboxylate toluene solution (2.2 M, 1.71 mL, 3.76 mmol) was slowly added dropwise thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the resulting residue was washed with hexane/dichloromethane (6/1 (v/v)), whereby the objective title compound was obtained as a yellow solid (351 mg, yield: 40%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=O)=[C:11]([NH2:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].O=[C:24]([CH3:35])[CH2:25][CH:26]([CH2:32][CH2:33][CH3:34])[C:27]([O:29][CH2:30][CH3:31])=[O:28].Cl[Si](C)(C)C.O>CN(C=O)C>[C:1]([N:4]1[CH2:5][C:6]2[S:12][C:11]3[N:13]=[C:24]([CH3:35])[C:25]([CH:26]([CH2:32][CH2:33][CH3:34])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)[C:10]=3[C:7]=2[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(sc(N)c2C(=O)c2ccc(C)cc2)C1
Reactant: CCCC(CC(C)=O)C(=O)OCC
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(C(=O)OCC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCN(C(C)=O)C3
Temperature: 100 °C
Yield: 94.4 %

Procedure:
To a solution of (6-acetyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p-tolyl)methanone (2 g; 6.36 mmol) and ethyl 4-oxo-2-propylpentanoate (1.3 g; 7 mmol) in dry DMF (25 mL) under nitrogen atmosphere was added chlorotrimethylsilane (3.25 mL; 25.45 mmol). The mixture was stirred in a sealed tube and heated at 100° C. for 48 h. After cooling, water (25 mL) was added and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of methanol (0-20%) in dichloromethane furnished 2.79 g (94%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][C:7](=O)[CH2:8]Br.[C:12]([NH:19][C:20]([NH2:22])=[NH:21])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[Na+].[I-]>CN(C=O)C>[C:15]([O:14][C:12]([N:19]1[CH:8]=[C:7]([CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:11])[N:21]=[C:20]1[NH2:22])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC(=N)N
Reactant: COC(=O)CCCC(=O)CBr
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
6-bromo-5-oxo-hexanoic acid methyl ester (2.30 g, 10.3 mmol), Boc-guanidine (4.92 g, 30.9 mmol),32 and NaI (3.07 g, 20.6 mmol) were dissolved in DMF (30 mL) and allowed to stir at room temperature. After 24 h the DMF was removed under reduced pressure and the residue was taken up in ethyl acetate (100 mL) and washed with water (3×50 mL) and brine (50 mL) before being dried (Na2SO4), filtered and evaporated to dryness. The resulting oil was purified by flash column chromatography (50-100% EtOAc/Hexanes) to obtain a yellow oil. Trituration of the viscous oil with cold hexanes (20 mL) produced a precipitate, which upon filtration yielded 18 (1.89 g, 65%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 6.53 (s, 1H), 5.6 (br s, 2H), 2.41 (t, 2H, J=7.2 Hz), 2.37 (t, 2H, J=7.2 Hz), 1.93 (quint., 2H, J=7.2 Hz), 1.58 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 174.09, 150.11, 149.61, 138.39, 107.15, 84.81, 51.56, 33.65, 28.18, 27.68, 23.82; HRMS (ESI) calcd for C13H22N3O4(MH)+ 284.1604. found 284.1606.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][C:5]2([CH3:14])[CH3:13].[H-].[Na+].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1)[C:7](=[O:12])[CH2:6][C:5]2([CH3:14])[CH3:13]
Reactant: CC1(C)CC(=O)Nc2ccc(Br)cc21
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CC(C)(C)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (0.5 g, 1.97 mmol) in THF (25 mL) was added 60% NaH (0.12 g, 2.95 mmol) suspended in mineral oil. The resulting reaction mixture was stirred at room temperature for 30 min., 4-methoxybenzyl chloride (0.34 g, 2.17) added, and heated under reflux for 20 h. The reaction was cooled to room temperature then quenched slowly with water. After extraction with ethyl acetate, the organic layer was dried (MgSO4), evaporated and the residue purified by chromatography (SiO2 3:7 ethyl acetate/hexane). The white crystalline product was obtained (0.35 g, 48%); mp 118-119° C., 1H NMR (DMSO-d6) δ 1.23 (s, 6H), 2.59 (s, 2H), 3.70 (s, 3H), 3.72 (s, 1H), 4.41 (d, 1H, J=5.8 Hz), 5.09 (s, 1H), 6.87 (m, 2H), 7.01 (d, 1H, J=8.78 Hz), 7.17 (d, 1H, J=8.98 Hz), 7.23 (d, 1H, J=8.79), 7.34 (dd, 1H, J=6.59 and 2.2 Hz), 7.43 (d, 1H, J=2.2 Hz); MS (APCI(+)) [M+H]+=374/376.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O)#[N:2].[C:19]([O:23][C:24](=[O:37])[CH:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[C:30]([F:36])[CH:29]=1)[CH3:26])([CH3:22])([CH3:21])[CH3:20].O1C2C=CC(OC3N=CC=CC=3C(O)=O)=CC=2OC1.COC(=O)COC1C=CC(CN)=C(F)C=1>>[C:19]([O:23][C:24](=[O:37])[CH:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:9]([C:8]2[C:7]([O:6][C:5]3[CH:16]=[CH:17][CH:18]=[C:3]([C:1]#[N:2])[CH:4]=3)=[N:15][CH:14]=[CH:13][CH:12]=2)=[O:11])=[C:30]([F:36])[CH:29]=1)[CH3:26])([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(Oc1ccc(CN)c(F)c1)C(=O)OC(C)(C)C
Reactant: N#Cc1cccc(Oc2ncccc2C(=O)O)c1
Agent: COC(=O)COc1ccc(CN)c(F)c1
Agent: O=C(O)c1cccnc1Oc1ccc2c(c1)OCO2
Product: CC(Oc1ccc(CNC(=O)c2cccnc2Oc2cccc(C#N)c2)c(F)c1)C(=O)OC(C)(C)C

Procedure:
The compound of Formula (5.0.25) was prepared in a manner analogous to that described in Preparation 20, substituting 2-(3-cyano-phenoxy)-nicotinic acid and (+)-2-(4-aminomethyl-3-fluoro-phenoxy)-propionic acid tert-butyl ester for the corresponding 2-(benzo-[1,3]-dioxol-5-yloxy)-nicotinic acid and (4-aminomethyl-3-fluoro-phenoxy)-acetic acid methyl ester materials, respectively.
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:3](=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=O)[NH:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=32)[CH2:2]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:28]2)=CC=1>C1(C)C=CC=CC=1>[CH2:1]1[N:12]2[C:13]3[C:3](=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[S:28])[NH:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=32)[CH2:2]1
Reactant: O=C1Nc2ccccc2N2CCc3cccc1c32
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C1Nc2ccccc2N2CCc3cccc1c32
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To 1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin6-one (67 g) in 1 l of toluene, under nitrogen, was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (45 g). The mixture was refluxed for 1 hr and allowed to stand overnight. The precipitate was collected and recrystallized from chloroform to afford 43 g, (60.2%) of product, mp 185°-186° C.