Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:8][CH3:9])=[N:4][N:5]([CH3:7])[CH:6]=1.[Cl:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([O:18][CH3:19])[C:12]=1[C@H:20]([C:22]1[C:30]2[C:25](=[N:26][CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=2)[NH:24][CH:23]=1)[CH3:21].C(=O)([O-])[O-].[K+].[K+].ClCCl>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].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.O1CCOCC1>[Cl:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([O:18][CH3:19])[C:12]=1[C@H:20]([C:22]1[C:30]2[C:25](=[N:26][CH:27]=[C:28]([C:2]3[C:3]([O:8][CH3:9])=[N:4][N:5]([CH3:7])[CH:6]=3)[CH:29]=2)[NH:24][CH:23]=1)[CH3:21]
Reactant: COc1nn(C)cc1Br
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cn(C)nc3OC)cc12
Temperature: 100 °C

Procedure:
A solution of 4-bromo-3-methoxy-1-methyl-1H-pyrazole (0.0399 g, 0.209 mmol), 3-[(S)-1-(2-chloro-3-fluoro-6-methoxy-phenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.0300 g, 0.0697 mmol), potassium carbonate (0.0289 g, 0.209 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride.dichloromethane (2.84 mg, 0.00348 mmol) in previously degassed 4:1 dioxane:water (1.50 mL) was evacuated and charged with N2 (2×) and heated under microwave conditions [Biotage, 100° C., 30 min, high absorption]. The reaction mixture was charged with an additional amount of 4-bromo-3-methoxy-1-methyl-1H-pyrazole (0.0399 g, 0.209) followed by Pd(PPh3)4 (4.02 mg, 0.00348 mmol) and evacuated and charged with N2 gas (3×) and heated under microwave conditions [Biotage, 100° C., 45 min, high absorption]. The dioxane layer was removed and diluted with CHCl3 and charged with silica gel. The sample was then dry loaded and purified by chromatography on silica gel [ISCO Combiflash, 12 g cartridge, 100% DCM→5% MeOH in DCM]. This resulted in the title compound as an off-white solid. 1H NMR (400 MHz, CD3OD): δ=1.78 (d, J=7.1 Hz, 3H), 3.75 (s, 3H), 3.93 (s, 3H), 5.07 (q, J=6.8 Hz, 1H), 6.83-6.91 (m, 1H), 7.09 (dd, J=8.8, 8.8 Hz, 1H), 7.27 (d, J=1.0 Hz, 1H), 7.65 (s, 1H), 7.83 (br. s., 1H), 8.27 (d, J=2.0 Hz, 1H). MS (ES+): m/z 415.06, 417.07 (76/24) [MH+]. HPLC: tR=3.97 min (polar—5 min, ZQ3).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])C)(C)(C)C.Cl.C(OCC)(=O)C>ClCCl>[CH3:6][NH:7][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:19])=[O:20]
Reactant: CN(CCc1ccccc1NS(=O)(=O)c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNCCc1ccccc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 128.2 %

Procedure:
N-[2-(2-(Phenylsulfonylamino)phenyl)ethyl]-N-methylcarbamic acid tert-butyl ester (547 mg, 1.4 mmol) was dissolved in dichloromethane (5 ml). 3.1 N hydrogen chloride in ethyl acetate (3 ml, 9.3 mmol) was added. The solution was stirred at room temperature for 1 h. Another portion of 3.1 N hydrogen chloride in ethyl acetate (5 ml, 15.3 mmol) was added. The solution was stirred for another 3.5 h. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silcia (7 g), using dichloromethane/methanol/25% aqueous ammonia 50:10:1 as eluent, to give 521 mg of N-[2-(2-(methylamino)ethyl)phenyl]benzenesulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[C:42]([F:45])[C:43]=1[F:44].[F-].[Cs+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:16][CH:15]=1)=[C:8]([C:40]1[CH:39]=[C:38]([F:37])[C:43]([F:44])=[C:42]([F:45])[CH:41]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cc(F)c(F)c(F)c3)ccc2c1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-yl ester (800 mg, 1.52 mmol), 3,4,5-trifluorobenzene boronic acid (804 mg, 4.57 mmol) and cesium fluoride (1.1 g, 7.6 mmol) and purge with nitrogen. In a separate flask, charge palladium(II)acetate (34 mg, 0.15 mmol) and tricyclohexylphosphine (64 mg, 0.23 mmol) and purge with nitrogen. Add degassed acetonitrile and sonicate under nitrogen for 10 minutes. Add the catalyst solution to the solids and plunge into an 80° C. oil bath for 10 minutes. Cool to room temperature and filter through celite. Concentrate and redissolve in methylene chloride. Wash with saturated aqueous sodium bicarbonate, separate, dry, filter and concentrate. Purify the residue over silica gel, eluting with 0 to 5% methanol in methylene chloride, to yield 720 mg (93%) of the title compound: mass spectrum (ion spray) 508.3 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:7]([CH3:18])[C:8]([C:11]2[S:15][C:14]([CH3:16])=[N:13][C:12]=2[CH3:17])=[N:9][N:10]=1.C([O-])([O-])=O.[K+].[K+].Cl.[Cl:26][C:27]1[CH:28]=[C:29]2[C:37](=[CH:38][CH:39]=1)[C:32]1([CH2:36][CH2:35][NH:34][CH2:33]1)[CH2:31][CH2:30]2.[Na+].[I-]>CN1C(=O)CCC1.O>[Cl:26][C:27]1[CH:28]=[C:29]2[C:37](=[CH:38][CH:39]=1)[C:32]1([CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][S:5][C:6]3[N:7]([CH3:18])[C:8]([C:11]4[S:15][C:14]([CH3:16])=[N:13][C:12]=4[CH3:17])=[N:9][N:10]=3)[CH2:33]1)[CH2:31][CH2:30]2
Reactant: Cc1nc(C)c(-c2nnc(SCCCCl)n2C)s1
Reactant: Clc1ccc2c(c1)CCC21CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nc(C)c(-c2nnc(SCCCN3CCC4(CCc5cc(Cl)ccc54)C3)n2C)s1
Reaction time: 0.17 h
Yield: 52.3 %

Procedure:
To a solution of 5-(5-(3-chloropropylthio)-4-methyl-4H-1,2,4-triazol-3-yl)-2,4-dimethylthiazole (Prep28, 70 mg, 0.23 mmol) in dry NMP (1 ml), K2CO3 (0.144 g, 1 mmol) was added and stirred for 10 min, then 5-chloro-2,3-dihydrospiro[indene-1,3′-pyrrolidine]hydrochloride (Prep10, 88 mg, 0.36 mmol) and NaI (0.07 g) were added and stirred for 23 h at 65° C. Water was then added and the solution was extracted with ethyl acetate (2×10 ml). The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by P-HPLC (TLC analysis performed by eluting with EA/MeOH 80:10) to give 57 mg of the title compound (y=52%).
Reaction SMILES: [CH:1]1(/[C:7](/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:8]/[CH:9]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH3:22])=[O:20]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:22][O:21][C:19](=[O:20])/[CH:23]=[CH:9]/[CH:8]=[C:7](/[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)\[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(/C(=C\C=O)C2CCCCC2)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C=C/C=C(\c1ccc(OC)cc1)C1CCCCC1
Yield: 63.5 %

Procedure:
As in Example 99, (Z)-3-cyclohexyl-3-(4-methoxyphenyl)-2-propenal (7.3 g) was reacted with (carbomethoxymethylene)triphenylphosphorane (11 g) in carbon tetrachloride (40 mL) and dichloromethane (4 mL) overnight at room temperature. The crude ester, isolated in the normal fashion, was purified by HPLC (ether-hexane; 1:7) to yield 5.7 g of (2E,4Z)-5-cylcohexyl-5-(4-methoxyphenyl)-2,4-pentadienoic acid methyl ester. A portion was crystallized from hexane to give the analytical specimen, mp 70.5°-72° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:13]([OH:15])[CH3:14]>CCOCC>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([O:15][CH2:13][CH3:14])=[O:5]
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1Cl
Reactant: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cc(F)c(Cl)cc1Cl
Temperature: 17 °C
Reaction time: 17 h
Yield: 90.8 %

Procedure:
A 25-mL round-bottom flask was equipped with a magnetic stir bar, thermometer, nitrogen inlet, addition funnel, and a reflux condenser. The flask was charged with 2,4-dichloro-5-fluorobenzoyl chloride (5.38 g, 23.65 mmol) and ethyl ether (5.0 g). The resulting colorless solution was cooled to 17° C. using a cool water bath. Ethanol (3.20 g, 69.47 mmol; absolute grade) was added dropwise from the addition funnel over ten minutes. Once the addition was complete, the solution was warmed to room temperature and stirred overnight (17 hours). Additional ether (20 mL) was added to the reaction mixture, which was then transferred to a separatory funnel. The reaction mixture was washed twice with 2% sodium hydroxide solution (10 mL), then with water (10 mL). The upper organic layer was separated and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was dried in a vacuum oven to give 5.09 g of ethyl 2,4-dichloro-5-fluorobenzoate as a pale yellow oil.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=[O:7])(C)(C)C.[F:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=1)C(Cl)=O>>[F:44][C:45]1[CH:53]=[C:52]([C:6]([NH:8][C@@H:9]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@@H:11]([CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]3)[CH2:10]2)=[O:7])[CH:51]=[CH:47][CH:46]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)c3cccc(F)c3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 34 in Step A and 3-fluorobenzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:24][C:25]([F:42])([F:41])[C:26]1[CH:27]=[C:28]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH:29]=[CH:30][C:31](O)=[O:32].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:24][C:25]([F:41])([F:42])[C:26]1[CH:27]=[C:28]([CH:29]=[CH:30][C:31]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=2)=[O:32])[CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1
Reactant: O=C(O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 70.3 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), 3,5-bis(trifluoromethyl)cinnamic acid (3.5 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (3.4 g, 70%) as an oily product.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[C:24]([O:26]C)=O)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH3:28].CO>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[C:24]([NH2:28])=[O:26])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(C(=O)OC)cccc2c1Nc1ccccc1C
Reactant: N
Solvent: CO
Product: CCCC(=O)c1cnc2c(C(N)=O)cccc2c1Nc1ccccc1C
Yield: 49 %

Procedure:
Methyl 3-butyryl-4-(2-methylphenylamino)quinoline-8-carboxylate (1.03 g, 2.8 mmol) and saturated methanol ammonia (50 ml) were heated to 140° in a pressure vessel for 4 hours. The solid which crystallised on cooling was filtered off and recrystallised from ethanol to give 3-butyryl-4-(2-methylphenylamino)quinoline-8-carboxamide (0.48 g, 49%), m.p. 185-187° .
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:40]([C:36]2[CH:35]=[C:34]3[C:39](=[CH:38][CH:37]=2)[N:31]([CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:19]4[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:29][CH:28]=2)[C:32]([CH3:44])=[C:33]3[CH3:43])=[O:41])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N)c1cccc(F)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(F)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(3-fluorophenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 521 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1[CH:22]2[CH2:23][C:24](=O)[CH2:25][C:20]3[C:21]2=[C:16]([CH:17]=[CH:18][CH:19]=3)[NH:15]1>C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+].[Ti](Cl)(Cl)(Cl)Cl>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1[CH:22]2[CH2:23][CH:24]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH2:25][C:20]3[C:21]2=[C:16]([CH:17]=[CH:18][CH:19]=3)[NH:15]1
Reactant: C1COCCN1
Reactant: O=C1Cc2cccc3c2C(C1)C(c1ccccc1F)N3
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Fc1ccccc1C1Nc2cccc3c2C1CC(N1CCOCC1)C3

Procedure:
Morpholine (0.51 ml) was dissolved in an anhydrous chloroform (5 ml) and to the solution was added dropwise a solution of titanium tetrachloride (98 μl) in anhydrous chloroform (2 ml) under cooling with ice, followed by addition of the compound (0.34 g) obtained in Example 252. The mixture was heated to reflux for 30 minutes and allowed to cool. The reaction mixture was diluted with saturated aqueous solution of sodium hydrogencarbonate and extracted twice with methylene chloride. The organic layers were combined, washed twice with water and once with saturated aqueous solution of sodium chloride successively and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to yield 0.42 g of the titled compound as a crude brown oil. The compound was used in the subsequent reaction without further purification.
Reaction SMILES: [CH2:1]1[O:25][C:24]2[CH:23]=[CH:22][C:5]([C:6]([C:8]#[C:9][C:10]([O:12]CC3C=CC(OC)=CC=3)=[O:11])=[O:7])=[CH:4][C:3]=2[O:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]1[O:25][C:24]2[CH:23]=[CH:22][C:5]([C:6]([C:8]#[C:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=2[O:2]1
Reactant: COc1ccc(COC(=O)C#CC(=O)c2ccc3c(c2)OCO3)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C#CC(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
A solution of 36.3 g (107 mmol) of 4-methoxybenzyl 3-[3,4-(methylenedioxy)benzoyl]propiolate in 300 ml of methylene chloride was treated at room temperature with 6.4 ml (215 mmol) of anhydrous trifluoroacetic acid. The reaction mixture was stirred at room temperature until crystallization began, then cooled to 0° and stirred for a further 30 minutes. The separated crystals were filtered off under suction, washed with cold methylene chloride and dried in a high vacuum. There was obtained 3-(3,4-(methylenedioxy)benzoyl]propiolic acid of melting point 137°.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1.[CH2:16](Br)[CH:17]=[CH2:18]>>[CH2:18]([O:1][C:2]1[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1)[CH:17]=[CH2:16]
Reactant: CCC(=O)c1cc2c(cc1O)CCCC2
Reactant: C=CCBr
Product: C=CCOc1cc2c(cc1C(=O)CC)CCCC2
Yield: 108.4 %

Procedure:
The product of step (b) (14.5 g) was treated with allyl bromide (11.5 g) under the conditions of Example 1(a) to give the title compound (18.8 g) as a pale brown oil, whose structure was confirmed by MS and NR spectroscopy.
Reaction SMILES: [C:1]([C:5]1[C:6](I)=[C:7]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[CH:33]=[C:32]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:31]=[CH:30]3)[CH:8]=[C:9]([C:11]2[C:12]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:13][C:14]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:43]([Sn](CCCC)(CCCC)C=C)[CH2:44]CC.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC12CC3(C)P(C4C=CC=CC=4)C(C)(CC(C)(O3)O1)O2>CS(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([C:5]1[C:6]([CH:43]=[CH2:44])=[C:7]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[CH:33]=[C:32]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:31]=[CH:30]3)[CH:8]=[C:9]([C:11]2[C:12]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:13][C:14]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)Oc1ncc(-c2cc(-c3ccc4cc(NS(C)(=O)=O)ccc4c3)c(I)c(C(C)(C)C)c2)c(OC(C)(C)C)n1
Agent: [Pd]
Agent: CC12CC3(C)OC(C)(CC(C)(O1)P3c1ccccc1)O2
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CS(C)=O
Product: C=Cc1c(-c2ccc3cc(NS(C)(=O)=O)ccc3c2)cc(-c2cnc(OC(C)(C)C)nc2OC(C)(C)C)cc1C(C)(C)C

Procedure:
To a 5 mL microwave tube was added the product from Example 34 Part A (210 mg, 0.3 mmol), tributyl(vinyl)stannane (0.175 mL, 0.600 mmol), potassium phosphate (134 mg, 0.63 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (8.77 mg, 0.030 mmol) and tris(dibenzylideneacetone)dipalladium(0) (13.74 mg, 0.015 mmol) in dimethyl sulfoxide (3 mL). The mixture was purged with nitrogen for 5 minutes and microwaved at 100° C. for 1 hour. The reaction mixture was partitioned with ethyl acetate and 0.1 M HCl. The organic layer was washed with saturated NaHCO3, brine, dried (Na2SO4), filtered and the filtrate treated with 3-mercaptopropyl functionalized silica gel, filtered and concentrated in vacuo to give crude product which was purified by silica gel flash chromatography eluting with ethyl acetate/hexane (10% to 20%) to give the title compound.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11].I[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>>[Br:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:4]([CH:9]=1)[C:3]([OH:2])=[O:12]
Reactant: CCCCCCCI
Reactant: COC(=O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCOc1ccc(Br)cc1C(=O)O

Procedure:
5-Bromo-2-heptyloxy-benzoic acid was prepared by reacting 5-bromo-2-hydroxy-benzoic acid methyl ester (1.0 g, 4.32 mmol) with iodoheptane (1.46 g, 6.49 mmol) as per general procedure H with potassium carbonate (1.5 g, 10.8 mmol) added. The ester thus obtained was subjected to hydrolysis as per general procedure C to yield the 5-bromo-2-heptyloxy-benzoic acid (0.950 g).
Reaction SMILES: [BrH:1].[CH2:2]([N:5]([CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:14]([O:17]C)=[C:13]2[C:9]=1[CH2:10][C:11](=[O:19])[NH:12]2)[CH2:3][CH3:4].Br>>[BrH:1].[CH2:20]([N:5]([CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]2[C:9]=1[CH2:10][C:11](=[O:19])[NH:12]2)[CH2:21][CH3:22]
Reactant: CCCN(CCC)CCc1ccc(OC)c2c1CC(=O)N2
Agent: Br
Product: CCCN(CCC)CCc1ccc(O)c2c1CC(=O)N2
Yield: 75 %

Procedure:
A 0.284 g (0.765 mmole) portion of 4-(2-di-n-propylaminoethyl)-7-methoxy-2(3H)-indolone hydrobromide was placed in a flask and approximately 5 ml of constant boiling hydrobromic acid was distilled (from stannous chloride) directly into the flask. The resulting mixture was stirred at reflux under an argon atmosphere for 3 hours. Evaporation of the solvents produced a solid residue which was recrystallized twice from methanol-ethyl acetate to provide 0.206 g (75%) of 4-(2-di-n-propylaminoethyl)-7-hydroxy-2(3H)-indolone hydrobromide. m.p. 252°-254°.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:25][NH:26][CH3:27]>O1CCOCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:26]([CH3:27])[CH3:25])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(Cl)c2C1=O
Reactant: CNC
Solvent: C1COCCO1
Product: CN(C)Cc1nc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)no1

Procedure:
7.0 g 7-Chloro-3-(5-chloromethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo-[1,5-a][1,4]benzodiazepin-6-one were suspended under stirring and argon atmosphere in 70 ml 1,4-dioxane and 25.7 ml dimethylamine (33% in ethanol) were added over 60 minutes. The reaction mixture was stirred one more hour at r.t. and then the solvents were removed under reduced pressure at 35° C. The residue was partitioned between 50 ml dichloromethane and 20 ml deionized water. The phases were separated and the organic phase was washed twice with 20 ml deionized water. The aqueous phases were extracted separately with the same portion of 25 ml dichloromethane, twice. The combined organic extracts were dried (Na2SO4) and the solvent was removed under reduced pressure. Crude product: 8.0 g as a light yellow foam.
Reaction SMILES: C([O:4][C:5]1[CH:27]=[CH:26][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([S:18]([N:21]=[CH:22][N:23]([CH3:25])[CH3:24])(=[O:20])=[O:19])[CH:12]=2)=[O:10])=[C:7]([Cl:28])[C:6]=1[Cl:29])C=C.[C:30]1(OC2C=CC=CC=2)[CH:35]=CC=C[CH:31]=1>>[CH2:35]([C:27]1[C:5]([OH:4])=[C:6]([Cl:29])[C:7]([Cl:28])=[C:8]([CH:26]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([S:18]([N:21]=[CH:22][N:23]([CH3:25])[CH3:24])(=[O:20])=[O:19])[CH:12]=1)=[O:10])[CH:30]=[CH2:31]
Reactant: C=CCOc1ccc(C(=O)c2ccc(Cl)c(S(=O)(=O)N=CN(C)C)c2)c(Cl)c1Cl
Reactant: c1ccc(Oc2ccccc2)cc1
Product: C=CCc1cc(C(=O)c2ccc(Cl)c(S(=O)(=O)N=CN(C)C)c2)c(Cl)c(Cl)c1O

Procedure:
16.5 g (35 mmol) of 4-allyloxy-3'-dimethylaminomethyleneaminosulfonyl-2,3,4'-trichlorobenzophenone in 200 ml of diphenyl ether are heated at 210° to 215° C. for 1 hour, and the still warm mixture is poured in portions, with stirring, into 1.2 l of petroleum ether. The precipitate is filtered off, washed several times with petroleum ether and recrystallized from methanol. Colorless crystals, melting point 190°-193° C.