Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(COC)OC>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCOCC1

Procedure:
4-(2-Nitro-4-trifluoromethylphenyl)morpholine was prepared by reaction of 4-chloro-3-nitrobenzotrifluoride with equimolar amounts of morpholine and triethylamine in monoglyme. The resultant product melts at 37°-39° C.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:11]=[N:12][C:13]([F:41])=[CH:14][C:15]=1[C:16]1[C:21]2[S:22][C:23]([C:25]3[C:30]([F:31])=[CH:29][N:28]=[C:27]([NH:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][NH:37][C:36]4=[O:40])[N:26]=3)=[CH:24][C:20]=2[CH:19]=[CH:18][CH:17]=1)C)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:31][C:30]1[C:25]([C:23]2[S:22][C:21]3[C:16]([C:15]4[C:10]([CH2:9][NH:7][CH3:6])=[CH:11][N:12]=[C:13]([F:41])[CH:14]=4)=[CH:17][CH:18]=[CH:19][C:20]=3[CH:24]=2)=[N:26][C:27]([NH:32][CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][NH:37][C:36]2=[O:40])=[N:28][CH:29]=1
Reactant: CN(Cc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCN4CCNC4=O)ncc3F)sc12)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCN4CCNC4=O)ncc3F)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
Dissolve [4-(2-{5-fluoro-2-[2-(2-oxo-imidazolidin-1-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophen-7-yl)-6-fluoro-pyridin-3-ylmethyl]-methyl-carbamic acid tert-butyl ester (0.19 g, 0.32 mmol) in dry CH2Cl2 (1.4 mL) and CF3COOH (1.4 mL). Stir at room temperature for 1 hour. Remove solvent completely. Dilute the trifluoro-acetic acid salt with CH2Cl2. Wash with saturated NaHCO3 solution, water and saturated aqueous sodium chloride. Dry with MgSO4. After filtration, remove solvent. Dry in vacuo overnight to afford the title compound (0.12 g, 78%). MS (ES) m/z 495 [M+1]+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:21][CH2:20][C:19]2[C:22]([S:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][C:35](=[O:40])[C:34]4([CH3:42])[CH3:41])=[C:23]([Cl:26])[CH:24]=[CH:25][C:18]=2[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[Cl:26][C:23]1[CH:24]=[CH:25][C:18]2[CH2:17][CH2:16][NH:15][CH2:21][CH2:20][C:19]=2[C:22]=1[S:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35](=[O:40])[C:34]2([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCCc3ccc4c(c3)C(C)(C)C(=O)N4)c2CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)Nc2ccc(CCCSc3c(Cl)ccc4c3CCNCC4)cc21
Temperature: 25 °C

Procedure:
Add trifluoroacetic acid (0.2 mL, 2.6 mmol) to a solution of 3-tert-butoxycarbonyl-7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (257 mg, 0.5 mmol) in dichloromethane (5 mL) then stir at ambient temperature over the weekend. Concentrate in vacuo. Dissolve the residue in methanol and load onto an SCX column. Elute with methanol followed by 7M ammonia in methanol. Collect the basic fraction and concentrate in vacuo. Purify the residue by prep-LCMS [Supelco Discovery C18 column (21.2×100 mm, 5 μm packing), 25 mL/min flow rate, eluting with a water/acetonitrile gradient containing acetic acid as modifier over 12 min, fraction collection triggered by Electrospray MS] to give 7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a white solid (101 mg, 25% over 2 steps). MS (ES+) m/z: 415 (M+H)+.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].C[O-].[Na+].Cl[C:9]1[O:10][C:11]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:13]=1>CO>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]2[N:13]=[C:9]([S:4][CH2:1][CH2:2][CH3:3])[O:10][C:11]=2[CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=1
Reactant: CCCS
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCSc1nc(-c2ccc(Cl)cc2)c(CCC(=O)OC)o1

Procedure:
To a solution of 1-propylmercaptan (0.54 mL) in methanol (20 mL) was added sodium methoxide (1.1 g) and then methyl 3-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl]propionate (1.5 g) was added. The mixture was stirred with heating under reflux for 30 min. The reaction mixture was concentrated, diluted with water, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[4-(4-chlorophenyl)-2-(1-propylsulfanyl)-5-oxazolyl]propionate was obtained from a fraction eluted with hexane-acetone (9:1, volume ratio). 2N Aqueous sodium hydroxide solution (5 mL) and methanol (15 mL) were added to this ester form, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water and acidified with 2N aqueous hydrochloric acid solution. The precipitated crystals were collected by filtration and recrystallized from isopropyl ether to give 3-[4-(4-chlorophenyl)-2-(1-propylsulfanyl)-5-oxazolyl]propionic acid (1.0 g, yield 63%) as colorless prism crystals. melting point: 128–129° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([O:7][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:6])=[CH:3][C:2]=1[O:1][CH2:9][CH2:10][CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(C(=O)O)cc1O
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOC(=O)c1ccc(OC)c(OCCCCC)c1
Temperature: 90 °C
Yield: 198 %

Procedure:
3-Hydroxy-4-methoxybenzoic acid (9.6 g, 0.057 mol) was dissolved in DMF (90 ml), and to this solution were successively added 1-bromopentane (25.9 g, 0.17 mol, 3.0 eq) and anhydrous potassium carbonate (47.4 g, 0.34 mol, 6.0 eq). The mixture was stirred under heating at 90° C. for 3 hours. This reaction mixture was cooled to room temperature, and anhydrous potassium carbonate was filtered off. Water (200 ml) was added to the filtrate, and the mixture was extracted twice with ethyl acetate (200 ml). The organic layers were combined, washed with saturated brine (300 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane/ethyl acetate=15/1-10/1) to give pentyl 4-methoxy-3-pentyloxybenzoate (17.4 g, 98.8%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.C[O-].C([Sn+](CCCC)CCCC)CCC.C([O:31][C:32]([CH3:34])=[CH2:33])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[F-].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O>[O:31]=[C:32]([CH3:34])[CH2:33][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cccc(Br)c1
Reactant: C=C(C)OC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[Sn+](CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccc(CC(C)=O)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
A stirred mixture of methyl (3-bromophenyl)acetate (19.7 g, 86.0 mmol), tributyltin methoxide (37.1 mL, 129 mmol), isopropenyl acetate (14.2 mL, 129 mmol), palladium acetate (961 mg, 4.28 mmol), and tri-o-tolylphosphine (2.63 g, 8.64 mmol) in toluene (70 mL) was heated at 100° C. for 6 h. Aqueous potassium fluoride solution (4 M, 120 mL) and EtOAc (200 mL) were added and the resulting mixture was stirred overnight. The mixture was then filtered through Celite and the layers were separated. The organic layer was washed with water and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-8% MeOH in DCM) to give the title compound (11.8 g, 66% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH:9]([NH2:12])([CH3:11])[CH3:10].CCN(CC)CC>C1COCC1>[Cl:8][C:4]1[N:3]=[C:2]([NH:12][CH:9]([CH3:11])[CH3:10])[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)Nc1cncc(Cl)n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 52.1 %

Procedure:
To a mixture of 2,6-dichloropyrazine (5 g, 33.78 mmolm, Aldrich) and isopropyl amine (2.4 g, 50.67 mmol, Aldrich) in dry THF (5 mL) was added Et3N (2.5 mL) and the reaction was stirred at 60° C. for 12 h. The reaction was cooled to RT, treated with ice cold water (˜25 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was triturated with n-pentane to give 6-chloro-N-isopropylpyrazin-2-amine (3 g, 52.5%) as a white solid. MS (ESI, pos. ion) m/z: 172.0 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 7.81 (s, 1H), 7.64 (s, 1H), 7.46 (d, J=7.2 Hz, 1H), 3.93-3.88 (m, 1H), 1.15 (d, J=5.6 Hz, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]2=[CH:28][C:10]=1[CH2:11][C@H:12]([NH:65][C:66]([O:68][CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)=[O:67])[C:13](=[O:64])[NH:14][C@@H:15]([CH2:42][C@@H:43]([O:56][Si:57]([C:60]([CH3:63])([CH3:62])[CH3:61])([CH3:59])[CH3:58])[CH2:44][NH:45][C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[C:16](=[O:41])[NH:17][C@H:18]([C:31]([O:33]CC1C=CC=CC=1)=[O:32])[CH2:19][C:20]1[CH:29]=[C:24]2[CH:23]=[CH:22][C:21]=1[Cl:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.CO.[OH-].[Li+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]2=[CH:28][C:10]=1[CH2:11][C@H:12]([NH:65][C:66]([O:68][CH2:69][C:70]1[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=1)=[O:67])[C:13](=[O:64])[NH:14][C@@H:15]([CH2:42][C@@H:43]([O:56][Si:57]([C:60]([CH3:63])([CH3:62])[CH3:61])([CH3:59])[CH3:58])[CH2:44][NH:45][C:46]([O:48][CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)=[O:47])[C:16](=[O:41])[NH:17][C@H:18]([C:31]([OH:33])=[O:32])[CH2:19][C:20]1[CH:29]=[C:24]2[CH:23]=[CH:22][C:21]=1[Cl:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNC(=O)OCc1ccccc1)C[C@@H]1NC(=O)[C@@H](NC(=O)OCc2ccccc2)Cc2cc(ccc2OCc2ccccc2)-c2ccc(Cl)c(c2)C[C@@H](C(=O)OCc2ccccc2)NC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNC(=O)OCc1ccccc1)C[C@@H]1NC(=O)[C@@H](NC(=O)OCc2ccccc2)Cc2cc(ccc2OCc2ccccc2)-c2ccc(Cl)c(c2)C[C@@H](C(=O)O)NC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
220 mg (0.21 mmol) of the compound from Example 25C are dissolved in 11 ml of THF, and 3 ml each of water and methanol are added. After the addition of 10.2 mg (0.43 mmol) of lithium hydroxide the mixture is stirred at RT for 24 h. The reaction solution is then concentrated in vacuo, and the crude product is dried under high vacuum.
Reaction SMILES: Cl.[N:2]1([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.S(C1C=CC(C)=CC=1)(O[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N+:29]([O-:31])=[O:30])(=O)=O>>[N+:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][CH2:21][N:5]1[CH2:6][CH2:7][N:2]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)[CH2:3][CH2:4]1)([O-:31])=[O:30]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccccc2[N+](=O)[O-])cc1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Product: O=[N+]([O-])c1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Yield: 75 %

Procedure:
3-{4-[2-(2-Nitro-phenyl)-ethyl]-piperazin-1-yl}-1,2-benzisothiazole was prepared according to the general method as outlined in Preparation 2 starting with 3-piperazin-1-yl-benzoisothiazole hydrochloride (13.37 g, 52.4 mmol) and 2-nitrophenethyl tosylate (15.3 g, 47.7 mmol). The product was isolated via column chromatography to afford 13.08 g of a viscous, brown liquid. Yield 75%; MS (APCI): 369 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.[Cl:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].Cl>C(O)CCC>[ClH:23].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:29]=[CH:30][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:32][CH:33]=3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(OCCCCl)cc1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Product: NS(=O)(=O)c1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Yield: 63.3 %

Procedure:
This compound was prepared according to the procedure of Example 1. A mixture of 3.0 g (0.01 mole) of [α,α-bis(p-fluorophenyl)]-4-piperidinemethanol, 2.5 g (0.01 mole) of 4-(3-chloropropoxy)benzenesulfonamide, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave a gum as residue. The gum was converted to the hydrochloride with ethereal hydrogen chloride and the solid was recrystallized from absolute ethanol to yield 3.5 g (64%) of white solid, m.p. 152°-175° C.
Reaction SMILES: [Mg].II.Br[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CON(C)[C:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=[O:15]>O1CCCC1>[CH:5]1([C:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc(C(=O)N(C)OC)cc1
Reactant: BrC1CCCCC1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)C2CCCCC2)cc1
Reaction time: 1 h
Yield: 31.8 %

Procedure:
Magnesium turnings (324 mg, 13.5 mmol) were suspended in tetrahydrofuran (20 mL). A crystal of iodine was added. Bromocyclohexane (2.00 g, 12.26 mmol) was added dropwise. The mixture was refluxed for 2 hours. The mixture was then added to a −5° C. solution of methyl 4-(methoxy(methyl)carbamoyl)benzoate (456 mg, 2.04 mmol) in tetrahydrofuran (5 mL). The reaction was stirred 1 hour, maintaining an internal temperature below 0° C. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography gave methyl 4-(cyclohexanecarbonyl)benzoate (160 mg, 32%). 1H NMR (400 MHz, CDCl3, δ): 8.10-8.12 (m, 2H), 7.96-7.98 (m, 2H), 3.94 (s, 3H), 3.22-3.25 (m, 1H), 1.90-1.82 (m, 4H), 1.76-1.72 (m, 1H), 1.25-1.50 (m, 5H).
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:3]=1.[C:27]1(C)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(OB(O)O)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>O.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.C(O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:4]2[N:3]=[C:2]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:7]([C:8]#[N:9])=[CH:6][C:5]=2[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)c(Br)nc2-c2ccc(F)cc2)cc1
Reactant: Cc1ccccc1
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: OB(O)Oc1ccccc1
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2cc(C#N)c(-c3ccccc3)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 76 %

Procedure:
To a mixture of 0.1 g (0.23 mmol) of 2-bromo-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-pyridine-3-carbonitrile (Example 3), 10 ml of toluene and 4 ml of ethanol was added 34 mg (0.28 mMol) of phenylboric acid and a solution of 71 mg (0.52 mMol) of K2CO3 in 1 ml water. To the resulting reaction mixture was added 18 mg of tetrakis(triphenylphosphine)palladium. The mixture was held at reflux overnight, cooled to room temperature, poured into 75 ml of water and extracted with dichloromethane. The combined organic solutions were washed once with 10% NaOH solution, once with brine, dried over MgSO4 and evaporated to dryness to give a yellowish oil which crystallized upon standing. Trituration with ether gave 74.5 mg (76%) of a white powder: m.p. 230-231° C.
Reaction SMILES: C(Br)(Br)Br.[CH3:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15](OC)=O.[CH2:19]([NH2:22])[CH2:20][NH2:21].C[Al](C)C>>[NH:21]1[CH2:20][CH2:19][N:22]=[C:15]1[C:7]1[N:6]([CH3:5])[C:14]2[C:9]([CH:8]=1)=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: NCCN
Reactant: COC(=O)c1cc2ccccc2n1C
Agent: C[Al](C)C
Solvent: BrC(Br)Br
Product: Cn1c(C2=NCCN2)cc2ccccc21

Procedure:
A stirred suspension of methyl 1H-indole-2-carboxylate (5.0 g), dimethyl sulphate (9 ml) and potassium carbonate (10.4 g) in dry acetone (200 ml) was heated under reflux for 24 h. After cooling to room temperature 5% ammonia solution (50 ml) was added and the mixture stirred for 2 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane and water. The organic layer was dried and the solvent evaporated to give methyl 1-methyl-1H-indole-2-carboxylate (5.4 g) as a white solid; IR (CHBr3) max 1695 cm-1. The ester was treated with ethylenediamine and trimethylaluminium as described in Example 1(a). Purification via column chromatography on silica eluting with 5% v/v methanolic ammonia in dichloromethane gave 2-(2-imidazolin-2-yl)-1-methyl-1H-indole as a white solid. The hydrochloride salt was prepared as in Example 3 and that recrystallised from ethanol/diethyl ether; mp 290°-295° C. (decomp) (Literature mp 260°-280° C. (decomp) D. J. Hlasta, D. Luttinger, M. H. Perrone, M. J. Silbernagel, S. J. Ward and D. R. Haubrich, J. Med. Chem. 1967, 30, 1555).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:6]
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: Cc1ncc(C(CN)N2CCOCC2)cn1
Product: Cc1ncc(C(CNC(=O)c2c(F)cccc2Cl)N2CCOCC2)cn1

Procedure:
From 2-chloro-6-fluorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-morpholinoethanamine.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:4][CH:3]1[C:5]([NH:7][C:8](=[CH:16][CH2:17][CH2:18][CH3:19])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:6].[ClH:21].C[CH2:23][O:24]CC>>[CH3:1][C:2]1([CH3:20])[CH2:4][CH:3]1[C:5]([NH:7][C:8]([O:24][CH3:23])([CH:16]=[CH:17][CH2:18][CH3:19])[C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[O:6].[ClH:21]
Reactant: CCCC=C(NC(=O)C1CC1(C)C)C(=O)OC(C)(C)C
Reactant: CCOCC
Agent: Cl
Product: CCC=CC(NC(=O)C1CC1(C)C)(OC)C(=O)OC(C)(C)C
Reaction time: 17 h

Procedure:
A solution of 0.84 g (3.0 mmole) of t-butyl 2-(2,2-dimethylcyclopropanecarboxamido)-2-hexenoate in 10 ml of Et2O saturated with anhydrous HCl was allowed to stand at room temperature under a drying tube. After 17 hrs, the solution was evaporated, and the residual gum was dissolved in 10 ml of saturated NaHCO3. This solution was washed with an additional 15 ml of 0.5N HCl, then dried (MgSO4), filtered, and concentrated to give a viscous oil. The oil was crystallized from toluene. Yield of white crystals=0.32 g (47%), m.p. 119°-122°. TLC (4:1 toluene-AcOH) showed a single spot. NMR indicated essentially pure Z-isomer. (Note: Treatment of the methanol adduct, t-butyl 2-(2,2-dimethylcyclopropanecarboxamido)-2-methoxyhexenoate, with anhydrous HCl in Et2O under similar conditions gave the same product.)
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[O:23][C:22]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:21][CH:20]=4)[CH:17]=3)[NH:12][N:11]=2)=[O:8])=[CH:4][CH:3]=1.ClCCl>FC(F)(F)C(O)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[O:23][C:22]([C:24]([OH:26])=[O:25])=[CH:21][CH:20]=4)[CH:17]=3)[NH:12][N:11]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc3[nH]nc(NC(=O)c4ccc(Cl)s4)c3c2)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2ccc3[nH]nc(NC(=O)c4ccc(Cl)s4)c3c2)o1
Yield: 99.7 %

Procedure:
240 mg of tert-butyl 5-{3-[(5-chlorothiophene-2-carbonyl)amino]-1H-indazol-5-yl}furan-2-carboxylate are dissolved in 1 ml of trifluoroacetic acid and 3 ml of dichloromethane and stirred at room temperature for 24 hours. The batch is evaporated, the residue is stirred with dichloromethane, filtered off with suction and dried, giving 209 mg of 5-{3-[(5-chlorothiophene-2-carbonyl)amino]-1H-indazol-5-yl}furan-2-car-boxylic acid (“A20”) (quant.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[C:16]([CH3:17])=[CH:15][NH:14][C:13]=1[CH:18]=O>N1CCCCC1>[CH3:11][C:12]1[C:16]([CH3:17])=[CH:15][NH:14][C:13]=1[CH:18]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: Cc1c[nH]c(C=O)c1C
Solvent: C1CCNCC1
Product: Cc1c[nH]c(C=C2C(=O)Nc3ccccc32)c1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
A reaction mixture of 67.0 mg (0.5 mmoles) of oxindole, 73.0 mg (0.6 mmoles) of the 3,4-dimethylpyrrole-2-carboxaldehyde, and 2 drops of piperidine in 2 was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 87.7 mg (37%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:63][C:64]1[C:69]([F:70])=[CH:68][C:67]([Cl:71])=[CH:66][N+:65]=1[O-]>[Fe].C(O)(=O)C.CN(C=O)C>[Cl:71][C:67]1[CH:68]=[C:69]([F:70])[C:64]([NH:63][C:24]([C:16]2[C:17]3[O:21][C:20]([CH3:22])([CH3:23])[CH2:19][C:18]=3[C:12]3[NH:11][C:10]([NH:9][C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:14][C:13]=3[CH:15]=2)=[O:25])=[N:65][CH:66]=1
Reactant: Nc1c(F)cc(Cl)c[n+]1[O-]
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Agent: [Fe]
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)Cc2c(c(C(=O)Nc3ncc(Cl)cc3F)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 13.4 %

Procedure:
The title compound was prepared by following the procedure described for Example-121 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.200 g, 0.266 mmol), COMU (0.569 g, 0.663 mmol), DIPEA (0.732 g, 5.66 mmol), 2-amino-5-chloro-3-fluoropyridine 1-oxide (Intermediate-43, 0.095 g, 0.584 mmol), DMF (3.0 mL), iron powder (0.200 g, 3.57 mmol) and acetic acid (10.0 mL) to afford 0.018 g of the desired product. 1HNMR (DMSO-d6): δ 1.54 (s, 6H), 3.10 (s, 2H), 7.30 (m, 3H), 7.40 (m, 1H), 8.17 (d, J=9.3 Hz, 1H), 8.36 (s, 1H), 9.85 (s, 1H), 11.00 (2H); MS [M]+: 504.04.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:10](=[O:16])/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CC(=C(C)C(C1C=CC([Cl:31])=C(Cl)C=1)=O)C(O)=O>>[Cl:31][C:2]1[CH:3]=[C:4]([C:10](=[O:16])/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(=O)/C=C/C(=O)O)cc1F
Reactant: CC(C(=O)O)=C(C)C(=O)c1ccc(Cl)c(Cl)c1
Product: COc1ccc(C(=O)/C=C/C(=O)O)cc1Cl

Procedure:
(E)-4-(3'-fluoro-4'-methoxyphenyl)-4-oxo-2-butenoic acid, and 2,3-dimethyl-4-(3',4'-dichlorophenyl)-4-oxo-2-butenoic acid.