Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:18][NH:30][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2cc(F)ccc2F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)ccc1F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 61.1 %

Procedure:
Cis-methyl 2-(2,5-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.241 g, 5.85 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.234 g, 5.85 mmol) dissolved in water (2.000 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.358 mL, 5.85 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow semi-solid. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-20% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(2,5-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.259 g, 61%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.88-2.13 (m, 4H), 2.63-2.83 (m, 2H), 2.99-3.10 (m, 1H), 3.23-3.34 (m, 1H), 3.45 (s, 3H), 3.88-4.00 (m, 1H), 4.35-4.46 (m, 1H), 5.85 (d, 1H), 6.88-7.06 (m, 3H). MS m/z 353 (M+H)+
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([C:24]4[CH2:28][CH2:27][C:26](=[O:29])[CH:25]=4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1.C([SiH](CC)CC)C>[Pd]>[F:30][C:2]1([F:1])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH:24]4[CH2:28][CH2:27][C:26](=[O:29])[CH2:25]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1
Reactant: O=C1C=C(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)CC4)c(Cl)ccc3n2)CC1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Product: O=C1CCC(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)CC4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 126 using 6-chloro-2-(3-oxo-cyclopent-1-enyl)-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-amide, palladium on carbon and triethylsilane. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74-8.77 (bs, 1H), 8.13 (d, J=9.0 Hz, 1H), 7.96 (d, J=9.51 Hz, 1H), 7.76 (d, J=9.01 Hz, 1H), 7.66 (d, J=8.81 Hz, 1H), 4.71 (s, 1H), 3.80-3.83 (m, 1H), 3.31-3.41 (m, 2H), 2.60-2.72 (m, 2H), 2.41-2.50 (m, 1H), 2.31-2.40 (m, 2H), 2.00-2.12 (m, 3H), 1.89-1.97 (m, 2H), 1.68-1.76 (m, 4H). m/z: 437.3 [M+H]+
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[CH2:13][N:14]([C:16]3[C:17]([CH3:47])=[C:18]([CH3:46])[C:19]4[N:20]([C:22]([C:32]5[CH:37]=[CH:36][N:35]=[C:34]([NH:38]C(=O)OC(C)(C)C)[CH:33]=5)=[C:23]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[N:24]=4)[N:21]=3)[CH2:15][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.O.N>ClCCl>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH2:15][N:14]([C:16]3[C:17]([CH3:47])=[C:18]([CH3:46])[C:19]4[N:20]([C:22]([C:32]5[CH:37]=[CH:36][N:35]=[C:34]([NH2:38])[CH:33]=5)=[C:23]([C:25]5[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=5)[N:24]=4)[N:21]=3)[CH2:13][CH:11]2[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(N2CC3CN(Cc4ccccc4)CC3C2)nn2c(-c3ccnc(NC(=O)OC(C)(C)C)c3)c(-c3ccc(F)cc3)nc2c1C
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cc1c(N2CC3CN(Cc4ccccc4)CC3C2)nn2c(-c3ccnc(N)c3)c(-c3ccc(F)cc3)nc2c1C
Reaction time: 2 h

Procedure:
To a solution of 2.9 g (4.58 mmol) of tert-butyl {4-[6-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-(4-fluorophenyl)-7,8-dimethylimidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}carbamate in 30 mL of dichloromethane are added 6.8 mL of trifluoroacetic acid and the reaction is stirred for 2 hours. The medium is poured into 200 mL of water and the mixture is basified by addition of aqueous ammonia.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1(C)[O:17]C(=O)[CH2:15][C:14](=O)[O:13]1.N1C=CC=CC=1>C(Cl)Cl>[O:9]=[C:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:11][C:12]([O:13][CH2:14][CH3:15])=[O:17]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
To a solution of phenylacetyl chloride (1 mL, 7.56 mmol) was added dropwise a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (1.09 g, 7.56 mmol) and pyridine (1.3 mL) in CH2Cl2 (20 mL) at 0° C. The solution was stirred for 30 min at 0° C., then allowed to warm slowly to rt and stirred overnight. The reaction mixture was then washed with 10% aqueous HCl (2×10 mL). The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude residue was dissolved in EtOH (20 mL) and heated under reflux conditions for 4 h. The mixture was cooled to rt and then concentrated under reduced pressure. The resulting oil was purified by flash column chromatography (PE/EA=1/4) to afford the title compound (600 mg, 38%) as a yellow oil. [M+H] Calc'd for C12H14O3, 207; Found, 207.
Reaction SMILES: C([S:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1)(=O)C.C[S-].[Na+].Cl>CO>[SH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1
Reactant: CC(=O)SC1CCN(C(=O)OC(C)(C)C)C1
Agent: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(S)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
tert-Butyl 3-(acetylthio)pyrrolidine-1-carboxylate (200 mg, 0.81 mmol) was dissolved in MeOH (10mL) and sodium methanethiolate (57 mg, 0.81 mmol) was added. The reaction mixture was stirred at rt for 30 mins. HCl (1M solution) was added and the aqueous layer extracted with DCM. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated affording the title compound (0.163 g, 98.4%). 1H NMR (500 MHz, CDCl3): δ 1.44 (s, 9H), 1.68 (d, 1H), 1.75-1.84 (m, 1H), 2.22-2.28 (m, 1H), 3.13-3.23 (m, 1H), 3.30-3.40 (m, 2H), 3.47-3.57 (m, 1H), 3.67-3.74 (m, 1H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1.CN(C)C=O.[C:20](Cl)(=O)[C:21](Cl)=O.C(N(CC)CC)C>C(Cl)Cl.C(O)C>[CH2:20]([O:7][C:6]([C:5]1[C:4]([O:13][CH3:14])=[CH:3][C:2]([I:1])=[CH:10][C:9]=1[O:11][CH3:12])=[O:8])[CH3:21]
Reactant: COc1cc(I)cc(OC)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OC)cc(I)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a solution of 4-iodo-2,6-dimethoxybenzoic acid (603.0 mg, 1.96 mmol), synthesized by the process described in Reference Example 11, in methylene chloride (12 mL) were added dimethylformamide (0.020 mL, 0.26 mmol) and oxalyl chloride (0.26 mL, 3.0 mmol). After stirring at room temperature for 30 minutes, the resulting solution was poured into an ice-cold solution of triethylamine (0.50 mL, 3.6 mmol) in ethanol (10 mL). The reaction mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. A solution of the residue in diethyl ether was washed successively with water, 0.1 M hydrochloric acid and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield the title compound as a colorless oil (641.0 mg, yield: 97%).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][N:6]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=O.[Li+].[BH4-]>C1COCC1>[CH2:18]([O:17][C:15]([N:6]1[CH2:7][C@H:8]([O:10][Si:11]([CH3:12])([CH3:13])[CH3:14])[CH2:9][C@H:5]1[CH2:3][OH:2])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C)CN1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Reaction time: 3 h
Yield: 96 %

Procedure:
To (2S,4R)-4-Trimethylsilanyloxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester 1.50 g (4.22 mmol) in 5 mL of anhydrous THF under an atmosphere of Ar in an ice bath, was added 2.56 mL LiBH4 (2.0 M in THF, 5.12 mmol) drop-wise. The solution was stirred for 3 h. The mixture was quenched with 1 mL of Sat. NaHCO3 and EtOAc (50 mL). The organics were washed with Sat. NaHCO3 (2×50 mL). The organic layer was dried over Na2SO4 and the solution was concentrated to afford 1.31 g (96%) of (2S,4R)-2-Hydroxymethyl-4-trimethylsilanyloxy-pyrrolidine-1-carboxylic acid benzyl ester as clear oil. HPLC: Rt 2.87 min. (100% area). 1H NMR (CDCl3, 400 MHz) δ 7.26-7.20 (5H, m), 5.05 (2H, s), 4.47 (1H, d, J=7.4 Hz), 4.20 (1H, bs), 4.08 (1H, q, J=7.3 Hz), 3.64 (1H, t, J=9.1 Hz), 3.51-3.47 (1H, m), 3.41-3.35 (2H, m), 1.89-1.84 (1H, m), 1.57-1.52 (1H, m), 0.11 (9H, s). LCMS (ESI) (M+H+) m/z: 324.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]([CH2:8][Cl:9])=[O:7])[CH3:2].[CH3:11][O:12][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:14]=1[CH:15]=O.C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1.C(OCC)(=O)C.O>[CH2:1]([O:3][C:4](=[O:10])[C:5](=[CH:15][C:14]1[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:13]=1[O:12][CH3:11])[C:6](=[O:7])[CH2:8][Cl:9])[CH3:2]
Reactant: COc1cc(OC)c(OC)cc1C=O
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1cc(OC)c(OC)cc1OC)C(=O)CCl
Reaction time: 2 h
Yield: 28.6 %

Procedure:
42 g of 4-chloroacetoacetic acid ethyl ester, 50 g of 2,4,5-trimethoxybenzaldehyde, 2.5 ml of glacial acetic acid and 1 ml of piperidine were dissolved in 60 ml of benzene and the solution was boiled for two hours using a water separator. Although conversion was not yet complete, the mixture was worked up. It was diluted with 200 ml of ethyl acetate, extracted in each case three times with saturated sodium bicarbonate solution, water, 1 M citric acid solution and again with water, dried and evaporated. On fractional crystallization of the residue from methanol, first 20 g of pure product, as the E/Z mixture, and then 10.5 g of unreacted aldehyde could be crystallized. In addition to a large amount of product, the mother liquor still contained only a little aldehyde and, after preliminary purification by chromatography on silica gel, could likewise be crystallized. A further 25 g of product were obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[CH:12].[CH3:13][NH:14][CH3:15].C1COCC1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.CCOC(C)=O>[C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[NH:4][CH2:3][CH2:2][N:14]([CH3:15])[CH3:13])#[CH:12]
Reactant: C#Cc1ccccc1NCCCl
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#Cc1ccccc1NCCN(C)C
Temperature: 80 °C
Yield: 50 %

Procedure:
N-(2-Chloroethyl)-2-ethynylaniline (0.5 g, 2.79 mmol) in ACN (16 mL) was treated with 2M dimethylamine in THF (4.2 mL, 8.37 mmol), sodium iodide (1.25 g, 8.37 mmol), sodium carbonate (887 mg, 8.37 mmol) and heated in a sealed tube at 80° C. (oil bath temperature) for 15 h, with stirring. EtOAc was added (100 mL) and the organic phase was washed first with water (100 mL) and then with brine. Removal of the volatiles by evaporation, after drying over sodium sulfate and purification of the crude over silica gel (DCM/7N NH3 in MeOH 9/1) afforded the title compound (265 mg, 50%).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH3:9])[CH:3]=1.C([Li])CCC.[Si]([O:22][C:23]1[CH:24]=[C:25]([CH:41]=[CH:42][CH:43]=1)[C:26]([C:28]1[CH:40]=[CH:39][C:31]([C:32]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=1)=[O:27])(C(C)(C)C)(C)C.N1C=CC=CC=1>C(OCC)C>[CH3:9][C:4]1[CH:3]=[C:2]([C:26]([C:28]2[CH:40]=[CH:39][C:31]([C:32]([N:34]([CH2:35][CH3:36])[CH2:37][CH3:38])=[O:33])=[CH:30][CH:29]=2)([OH:27])[C:25]2[CH:41]=[CH:42][CH:43]=[C:23]([OH:22])[CH:24]=2)[C:7]([CH3:8])=[CH:6][N:5]=1
Reactant: CCN(CC)C(=O)c1ccc(C(=O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Reactant: Cc1cc(Br)c(C)cn1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCN(CC)C(=O)c1ccc(C(O)(c2cccc(O)c2)c2cc(C)ncc2C)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
A portion of the 4-bromo-2,5-dimethylpyridine (15.4 g, 83.0 mmol) was dissolved in 500 mL of anhydrous diethyl ether and chilled to -78° C. n-Butyllithium (52 mL, 1.6M in hexanes) was added dropwise and the resulting slurry was stirred for 30 minutes. 4-(3-((tert-butyldimethylsilyl)oxy)benzoyl)-N,N-diethylbenzamide (34.2 g, 83.0 mmol) was dissolved in 250 mL of anhydrous diethyl ether and chilled to -78° C. The lithiated pyridine was slowly transferred via cannula to the diarylketone solution. The temperature was allowed to rise to -40° C. for 4.5 hours. The reaction was quenched with saturated aqueous ammonium chloride. The diethyl ether layer was separated, the solvent was removed, and the residue was redissolved in 300 mL acetonitrile. Tetraethylammonium fluoride hydrate (19.8 g) was added, and the reaction was stirred overnight. The solvent was removed, and the residue was redissolved in 500 mL 1M hydrochloric acid and washed with 500 mL of diethyl ether. The pH of the aqueous solution was adjusted to 8 and the solution was extracted with dichloromethane. The solvent was removed and the residue was crystallized from acetonitrile to give 16.4 g (48%) of (±)-4-(α-(2,5-dimethyl-4-pyridyl)-α,3-dihydroxybenzyl)-N,N-diethylbenzamide.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1.[CH2:14]([O:16][C:17]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O)[CH3:15]>>[CH2:14]([O:16][C:17]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]1[N:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:9][CH:8]=2)[C:17](=[O:16])[CH:24]([F:25])[CH2:23]1)[CH3:15]
Reactant: CCOc1c(F)cccc1C=O
Reactant: NCc1ccc(OC(F)(F)F)cc1
Product: CCOc1c(F)cccc1C1CC(F)C(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedures 10A2 (GP10A2), 10B (GP10B), 10F (GP10F), and 10I (GP10I) using commercially available (4-(trifluoromethoxy)phenyl)methanamine and synthesized 2-ethoxy-3-fluorobenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.95 min.; [M+H]+: 415.87 g/mol.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:33]1([CH2:39][C:40](Cl)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[CH2:17][C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:40](=[O:41])[CH2:39][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1ccccc1)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.7 g, 4.3 mmol) was added to a stirred suspension of 3-[4-(aminomethyl)-1-oxo-1,3-dihydro-isoindol-2-yl]piperidine-2,6-dione hydrochloride (0.6 g, 1.9 mmol) in acetonitrile (50 mL). After stirring for 30 minutes, phenylacetyl chloride (0.4 g, 2.3 mmol) was added. The mixture was stirred at room temperature for 17 hours. Solvent was removed and the residue was stirred with water (40 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-phenyl-acetamide (0.41 g, 54%) as a white solid: mp 236-238° C.; 1H NMR (DMSO-d6) δ 1.94-1.98 (m, 1H, CH2), 2.15-2.19 (m, 1H, CH2), 2.49-2.63 (m, 1H, CH2), 2.85-2.99 (m, 1H, CH2), 3.47 (s, 2H, CH2), 4.23-4.43 (m, 4H, 2CH2), 5.07-5.14 (dd, J=5.1 and 13.2 Hz, 1H, CH), 7.18-7.33 (m, 5H, Ar), 7.46-7.64 (m, 3H, Ar), 8.61 (t, J=5.6 Hz, 1H, NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.51, 31.14, 42.23, 46.08, 51.47, 121.70, 126.34, 128.22, 128.95, 130.73, 131.69, 134.49, 136.16, 140.09, 167.99, 170.18, 170.87, 172.81; Anal. calcd. for C22H21N3O4+0.07H2O: C, 67.29; H, 5.43; N, 10.70. Found: C, 66.94; H, 5.22; N, 10.63.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]2[C:5]([CH:6]=[C:7]([C:16]([NH2:18])=O)[NH:8]2)=[CH:4][C:3]=1[O:19][C:20]1[CH:21]=[N:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>O1CCCC1>[F:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]2[C:5]([CH:6]=[C:7]([C:16](=[S:39])[NH2:18])[NH:8]2)=[CH:4][C:3]=1[O:19][C:20]1[CH:21]=[N:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: COCCOc1c(F)c(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=O)[nH]c12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COCCOc1c(F)c(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Temperature: 55 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A mixture of 6-fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide (0.61 g) and Lawesson's reagent (0.61 g) in tetrahydrofuran (25 mL) was stirred at 55° C. for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=40:60 to 70:30, volume ratio) to give light yellow crystals, which were washed with ethyl acetate-hexane to give the title compound (585 mg, 92%) as light yellow crystals. MS 440 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42](=[O:47])[C:43]([F:46])([F:45])[F:44])=[C:37]([I:48])[CH:36]=1.[C:49]([O:53][C:54]([N:56]1[CH2:61][CH:60]=[C:59]([CH2:62]O)[CH2:58][CH2:57]1)=[O:55])([CH3:52])([CH3:51])[CH3:50]>O1CCCC1>[C:49]([O:53][C:54]([N:56]1[CH2:57][CH:58]=[C:59]([CH2:62][N:41]([C:38]2[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][C:37]=2[I:48])[C:42](=[O:47])[C:43]([F:45])([F:46])[F:44])[CH2:60][CH2:61]1)=[O:55])([CH3:52])([CH3:50])[CH3:51]
Reactant: O=C(Nc1ccc(Cl)cc1I)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC=C(CO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(CN(C(=O)C(F)(F)F)c2ccc(Cl)cc2I)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 54.8 %

Procedure:
Triphenylphosphine (5.16 g) was dissolved in tetrahydrofuran (130 ml) and the solution was cooled to 0° C. under argon. Diisopropylazodicarboxylate (3.82 ml) was added dropwise over 10 min and the resulting mixture was stirred at 0° C. for 20 min (formation of a white precipitate). N-(4-Chloro-2-iodo-phenyl)-2,2,2-trifluoro-acetamide (5.5 g) was added as a solid, followed by 4-hydroxymethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (J. Org. Chem. 2001, 66, 5545-5551, 3.4 g) dissolved in a minimum volume of tetrahydrofuran. The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The solution was then concentrated in vacuo and the residue subjected to silica gel chromatography (cyclohexane:ethyl acetate 9:1) to afford 4-{[(4-chloro-2-iodo-phenyl)-(2,2,2-trifluoro-acetyl)-amino]-methyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4.7 g). 1H NMR (600 MHz, CDCl3) 1.5 (s, 9H), 2.20 (m, 2H), 3.49 (m, 1H), 3.50 (d, J=17 Hz, 1H), 3.55 (m, 1H), 3.8-3.9 (m, 1H), 5.02 (d, J=17 Hz, 1H), 5.40 (s, 1H), 7.0 (m, 1H), 7.38 (dd, 1H), 7.92 (d, 1H); MS (ES+) 445/447 (M+H+—CO2-isobutene), 486/488 (M+H+-isobutene).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([CH2:15]Cl)[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)CO>[Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([CH2:15][N:27]3[CH2:26][CH2:25][N:24]([C:21]4[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=4)[CH2:29][CH2:28]3)[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: FC(F)(F)c1cc(Cl)c2nc(CCl)cn2c1
Solvent: CCN(CC)CC
Solvent: OCCO
Product: Fc1ccc(N2CCN(Cc3cn4cc(C(F)(F)F)cc(Cl)c4n3)CC2)cc1
Temperature: 82.5 °C
Reaction time: 2.25 h
Yield: 64.8 %

Procedure:
A mixture of 8-chloro-2-(chloromethyl)-6-trifluoromethylimidazo[1,2-α]pyridine (0.341 g), 1-(4-fluorophenyl)piperazine (Aldrich; 0.264 g), triethylamine (Aldrich; 0.21 mL), and ethylene glycol (2 mL) is stirred for 2.25 h at 80-85° C. After cooling, the mixture is partitioned between water and dichloromethane and the combined inorganic layers are washed with brine, dried with MgSO4, and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (2/98) and the appropriate fractions combined, concentrated, and crystallized from ether/hexane to give 0.339 g of the title compound; mp 91-97° C.; MS m/z 412, 414; IR (mineral oil) 1322, 1161, 1153, 1512, 1171 cm-1 ; 1H NMR (CDCl3) δ2.76, 3.15, 3.87, 6.88, 6.96, 7.41, 7.75, 8.41.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[NH:9][C:10]=2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(=O)CC>[CH2:22]([N:9]1[C:10]2[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:6](=[O:15])[C:7]2=[CH:14][CH:13]=[CH:12][N:8]12)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: O=c1c2ccc(Cl)cc2[nH]n2cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=c1c2ccc(Cl)cc2n(Cc2ccccc2)n2cccc12
Reaction time: 2 h

Procedure:
To a slurry of 7-chloropyrrolo[1,2-b]cinnolin-10(5H)-one (35.0 g) and potassium carbonate (66.34 g) in 150 ml of 2-butanone was added benzyl bromide (44.47 g) and the mixture was stirred at 50° for 2 h. The reaction was quenched with 750 ml of H2O, and the mixture was neutralized with 2N HCl to pH 8 and extracted with chloroform. The organic layer was washed successively with dilute HCl, H2O and brine and thereafter dried (MgSO4), charcoaled, filtered and concentrated. The yellow-orange residue was purified by flash chromatography (silica, dichloromethane) and recrystallized from ethanol to give 12.0 g of light yellow microcrystals, mp 163°-165°.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[CH:15][N:14]([CH:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:18][C:19]([O:21]CC)=[O:20])[C:13]=3[CH:30]=2)=[O:7])=[CH:4][CH:3]=1>Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[CH:15][N:14]([CH:17]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:18][C:19]([OH:21])=[O:20])[C:13]=3[CH:30]=2)=[O:7])=[CH:31][CH:32]=1
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3ccc(N)cc3)cc21
Agent: Cl
Product: Nc1ccc(C(=O)Nc2ccc3ncn(C(CC(=O)O)c4ccccc4)c3c2)cc1

Procedure:
A solution of ethyl 3-{6-[(4-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (50 mg, 117 μmol) in hydrochloric acid (20 mL of a 5N solution) was stirred at room temperature for 72 hours. The solution was then evaporated in vacuo, and the residue was purified by RP-HPLC to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=3.20 min, MH+ 401].