Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH2:12][NH2:13].[N+:14]([C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][CH2:23][C:24]2=O)=[CH:19][CH:18]=1)([O-:16])=[O:15].C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH2:12][N:13]=[C:24]1[C:25]2[C:20](=[CH:19][CH:18]=[C:17]([N+:14]([O-:16])=[O:15])[CH:26]=2)[CH2:21][CH2:22][CH2:23]1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Reactant: NCCN1CCc2ccccc2C1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc2c(c1)C(=NCCN1CCc3ccccc3C1)CCC2
Temperature: 130 °C
Yield: 94 %

Procedure:
To a solution of 36 (964 mg, 5.48 mmol) and 7-nitro-3,4-dihydro-2H-naphthalen-1-one (95) (1.05 g, 5.48 mmol) in toluene (30 mL) was added a catalytic amount of TFA. The reaction was heated at 130° C. overnight before it was allowed to cool to room temperature and diluted with EtOAc (100 mL). The organic solution was sequentially washed with saturated NaHCO3 (aq. 100 mL), brine (100 mL), dried over Na2SO4, and concentrated to give 96 as a brown oil (1.8 g, 94%).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1>O1CCOCC1>[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: C1=COCC1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Yield: 55 %

Procedure:
Into 30 ml of dioxane were suspended 1.3 g of 5-fluorouracil. To this suspension were added 1.4 g of 2,3-dihydrofuran and the mixture was reacted in an autoclave for 5 hours at 170° C. After completion of the reaction, the reaction liquid was treated in the same manner as described in Example 1 whereby 0.40 g of the starting 5-fluorouracil was recovered as a substance insoluble in chloroform and 1.10 g of 1-(2-tetrahydrofuryl)-5-fluorouracil was obtained. The yield of the end product was 79.5% based on the consumed 5-fluorouracil.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42]C1C=CC=CC=1)(=[O:41])=[O:40])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51]C=1S(Cl)(=O)=O>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:34][CH:35]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([C:42]1[CH:51]=[CH:52][C:53]2[C:58](=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:49]=1)(=[O:40])=[O:41])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)c3ccc4ccccc4c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 53 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 6, Example 1) was added 2-naphthalenesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 53% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:30][NH:31][O:32][CH3:33].CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[CH3:4][C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:31]([CH3:30])[O:32][CH3:33])=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:7])([CH3:2])[CH3:3]
Reactant: CNOC
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-L-leucine (3.00 g, 13.0 mmol) in THF (25.0 mL) was added 1,1′-carbonyldiimidazole (2.52 g, 15.6 mmol) portionwise over about 10 min. After stirring 1 h at RT, a solution of N,O-dimethylhydroxylamine hydrochloride (1.39 g, 14.3 mmol) and DIPEA (2.49 mL, 14.3 mmol) in DMF (6.0 mL) was added. The reaction mixture was stirred for 2.5 h at RT, followed by concentration in vacuo. The residue was diluted with EtOAc (50 mL) and washed with 1 M aq. HCl (2×20 mL), saturated aq. NaHCO3 (2×20 mL), and brine (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound (2.34 g, 66%) as a clear, colorless oil. LC-MS m/z 275 (M+H)+, 1.17 min (ret time).
Reaction SMILES: [CH2:1]([O:4][NH:5][C@@H:6]1[CH:11]=[C:10]([CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:9]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[NH:8][CH2:7]1)[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.Cl[C:41](Cl)([O:43]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:4][N:5]1[C:41](=[O:43])[N:8]2[CH2:7][C@H:6]1[CH:11]=[C:10]([CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:19])[CH3:20])([CH3:16])[CH3:17])[C@H:9]2[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH:2]=[CH2:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCON[C@@H]1C=C(CCO[Si](C)(C)C(C)(C)C)C(CO[Si](C)(C)C(C)(C)C)NC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CCON1C(=O)N2C[C@H]1C=C(CCO[Si](C)(C)C(C)(C)C)[C@H]2CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 260 %

Procedure:
To a solution of O-allyl-N-((3R)-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3,6-tetrahydropyridin-3-yl)hydroxylamine (Intermediate 284, 3.95 g, 8.65 mmol) and diisopropylethyl amine (6.02 mL, 34.58 mmol) in acetonitrile (600 mL) at 0° C. was added triphosgene (0.871 g, 2.94 mmol) as a solution in acetonitrile (26 mL). The triphosgene solution was added at a rate of 4 mL/hour. Once addition was complete the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and 1:1 brine:water. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-30% ethyl acetate/hexanes) afforded the title compound as a yellow oil (3.69 g, 88%). This reaction was run in two separate 1 L flasks due to the large volume and combined for work up and purification.
Reaction SMILES: [C:1]([CH:3]=[CH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]([NH:15][C:16](=[O:38])[CH2:17][CH:18]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)(=[O:29])=[O:28])[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:10][CH2:9][CH2:8]2)#[N:2].C(Cl)(Cl)Cl>CCO.O=[Pt]=O>[NH2:2][CH2:1][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]([NH:15][C:16](=[O:38])[CH2:17][CH:18]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)(=[O:29])=[O:28])[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[CH2:10][CH2:9][CH2:8]2
Reactant: N#CC=Cc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1ccc(Cl)c(Cl)c1)c1ccc(F)cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: NCCCc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1ccc(Cl)c(Cl)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-[6-(2-Cyano-vinyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-(3,4-dichloro-benzenesulfonylamino)-3-(4-fluoro-phenyl)-propionamide (150 mg, 0.26 mmol) in EtOH:CHCl3 mixture (75:25, 10 mL) was added PtO2 (18 mg, 0.078 mmol). The resulting mixture was flushed under N2 gas followed by evacuating—this was done 3 times. After last evacuation, the hydrogen balloon was inserted. The reaction mixture was stirred under H2 at RT for 2 h. Solvent was separated from the PtO2 by passing through the Celite®. Solvent was evaporated in vacuo to give the final product. MS m/z: 579.11 (M+H). Calc'd. for C28H30Cl2FN3O3S-578.53.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH:8]2C(=O)O[C:11](C)(C)[O:10][C:9]2=[O:17])=[CH:6][C:5]([CH3:18])=[N:4]1)[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.O.C(N(CC)CC)C>CO>[CH3:11][O:10][C:9](=[O:17])[CH2:8][C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:18])[CH:6]=1
Reactant: CCn1nc(C)cc1C1C(=O)OC(C)(C)OC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: CCn1nc(C)cc1CC(=O)OC
Temperature: 60 °C
Yield: 69.7 %

Procedure:
5-(2-Ethyl-5-methyl-2H-pyrazol-3-yl)-2,2-dimethyl-[1,3]dioxane-4,6-dione (11.05 g, 43.8 mmol) was dissolved in anhydrous methanol (125 ml) followed by the addition of p-TsOH×H2O (36.68 g, 192.85 mmol). The resulting reaction mixture was heated to 60° C. for 75 minutes, cooled to 0° C. and triethylamine (26.85 ml, 192.9 mmol) was added drop by drop over a period of 20 minutes. The resulting mixture was concentrated under reduced pressure. The residue was taken into DCM (200 ml) and washed with water (2×75 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silicagel, DCM/methanol=30/1) to give 5.56 g (70%) of (2-ethyl-5-methyl-2H-pyrazol-3-yl)-acetic acid methyl ester. LC-MS: tR 0.62 min; [M+H]+=183.18.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:3]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)n3ccnc23)CC1
Reactant: OB(O)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccs3)n3ccnc23)CC1
Temperature: 90 °C
Yield: 69.3 %

Procedure:
A 100 mL round bottom flask was charged with tert-butyl 4-(5-bromoimidazo[1,2-a]pyrazin-8-yl)piperazine-1-carboxylate (1.0 g, 2.62 mmol), thiophen-2-ylboronic acid (0.50 g, 3.93 mmol), Pd(PPh3)2Cl2 (200 mg, 0.26 mmol), Cs2CO3 (0.60 g, 3.93 mmol) and DMF (30 mL). After air was purged by bubbling N2 into the reaction solution, the reaction mixture was heated at 90° C. for 30 h. Work-up: the reaction mixture was poured into water (150 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 10% EtOAc in petroleum ether, to afford 0.70 g (72%) of the product as a yellow solid. MS m/z: 386 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH3:13][NH:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1.C1C=CC2N(O)N=NC=2C=1.O.CCN(CC)CC.C(Cl)CCl>CN(C=O)C.C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:14]([CH3:13])[CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: CNCc1ccc2ccccc2c1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(Cc1ccc2ccccc2c1)C(=O)/C=C/c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.8 %

Procedure:
To a stirred solution of (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.30 g, 1.8 mmole) in 1:1 DMF/CH2Cl2 (25 mL) was added 2-(methylaminomethyl)naphthalene (0.34 g, 2 mmole), HOBt.H2O (0.27 g, 2 mmole), Et3N (0.28 mL, 2 mmole), and EDC (0.38 g, 2 mmole). After stirring at RT for 16 hr the reaction was concentrated under vacuum. The residue was taken up in ethyl acetate and the solution was washed with H2O, dried (Na2SO4) and concentrated to dryness. Purification by flash chromatography on silica gel (4% methanol/CHCl3), trituration with 1:1 ethyl acetate/hexane, filtration, and drying under vacuum gave the title compound (0.49 g, 81%) as an off-white solid: LCMS (ES) m/e 318.0 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])=[CH:10][CH:9]=1)=[O:6].[OH-].[NH4+:27]>>[F:24][C:17]1[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=1[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:27])=[O:2])=[CH:9][CH:10]=1
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2cc(F)c(F)cc2F)cc1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)CC(=O)Nc1ccc(OCc2cc(F)c(F)cc2F)cc1
Yield: 52 %

Procedure:
Prepared in analogy to example 3 from N-[4-(2,4,5-trifluoro-benzyloxy)-phenyl]-malonamic acid methyl ester and ammonium hydroxide. Yield=52%. Colorless solid. MS: m/e=339.2 (M++H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]3[CH2:29][CH2:28][C:27](=[CH:30][C:31]([OH:33])=[O:32])[CH2:26][CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[OH-].[Na+].C(O)C.O>[Pd].C(O)(=O)C>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9][N:8]([CH:24]3[CH2:25][CH2:26][CH:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:28][CH2:29]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(=CC(=O)O)CC1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(CC(=O)O)CC1
Reaction time: 20 h
Yield: 84.6 %

Procedure:
A mixture of 2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyliden}acetic acid (0.60 g, 1.36 mmol), 10% palladium on activated carbon (0.18 g), 1M aqueous sodium hydroxide (9 mL) and ethanol (60 mL) was hydrogenated under an atmosphere of hydrogen (60 psi) for 20 hours and filtered through a pad of celite. The filtrate was evaporated under reduced pressure to yield a white solid which was taken into water (20 mL) followed by addition of 1M acetic acid (20 mL) to precipitate the product. The suspension was then filtered and the solid was lyophilized to yield 2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}acetic acid (0.51 g, 1.15 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 11.99(br, 1H), 8.13(s, 1H), 7.60 (s, 1H), 7.49(d, 2H), 7.41(t, 2H), 7.15(t, 1H), 7.09(m, 4H), 6.09(br, 2H), 4.60 (m, 1H), 2.20-1.24(m, 11H); RP-HPLC (Hypersil C18, 5 μm, 100 A, 250×4.6 mm; 25%-100% acetonitrile-0.05M ammonium acetate over 10 min, 1 mL/min) Rt 9.62 min. MS: MH+ 443.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:9]1[CH:10]=[C:11]([NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH:12]=[CH:13][C:14]=1[NH:15]C(=O)C(F)(F)F)#[N:8]>CO.O>[NH2:15][C:14]1[CH:13]=[CH:12][C:11]([NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])=[CH:10][C:9]=1[C:7]#[N:8]
Reactant: N#Cc1cc(NC(=O)c2ccccc2F)ccc1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#Cc1cc(NC(=O)c2ccccc2F)ccc1N

Procedure:
Potassium carbonate (5.0 g) is added to a solution of N-[3-cyano-4-(2,2,2-trifluoroacetyl-amino)-phenyl]-2-fluoro-benzamide (2.5 g) in methanol (270 mL) and water (16 mL) and the mixture is refluxed overnight. After removing the solvent under reduced pressure, the residue is suspended in water and extracted with dichloromethane. The organic extracts are pooled, washed with water and then saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide the desired compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1[N:14]1[C:18](=[O:19])[C:17]2=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=[C:16]2[C:15]1=[O:25])[CH3:2].[H][H]>C(OCC)(=O)C.[Rh]>[CH2:1]([O:3][CH2:4][C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:6]=1[N:14]1[C:18](=[O:19])[C:17]2=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=[C:16]2[C:15]1=[O:25])[CH3:2]
Reactant: [H][H]
Reactant: CCOCc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Agent: [Rh]
Solvent: CCOC(C)=O
Product: CCOCc1cc(N)ccc1N1C(=O)c2ccc(Cl)cc2C1=O

Procedure:
The solution of 300 mg of N-(2-ethoxymethyl-4-nitrophenyl)-4-chlorophthalimide in 40 ml of ethyl acetate is hydrogenated with 200 mg of 5% rhodium on carbon at 2.5 atmospheres of hydrogen pressure for 3 hours. After filtration from the catalyst the residue is refluxed for 24 hours in 5 ml of xylene, the solution evaporated and the residue crystallized from diethyl ether, to give the N-(2-ethoxymethyl-4-aminophenyl)-4-chlorophthalimide melting at 154°-156°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][C:13](=[O:15])[CH3:14])=[C:7]([O:16][CH3:17])[C:6]([O:18][CH3:19])=[C:5]2[O:20]C(=O)C.P([O-])([O-])([O-])=O.P([O-])([O-])(O)=O.[Na+].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][C:13](=[O:15])[CH3:14])=[C:7]([O:16][CH3:17])[C:6]([O:18][CH3:19])=[C:5]2[OH:20]
Reactant: COc1c(OC)c(OC(C)=O)c2cc(Cl)ccc2c1OC(C)=O
Agent: O=P([O-])([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1c(OC)c(OC(C)=O)c2ccc(Cl)cc2c1O
Yield: 22.8 %

Procedure:
Ten grams of 6-chloro-2,3-dimethoxy-1,4-diacetyloxynaphthalene, 150 ml of 0.05M, pH 8, phosphate buffer solution and 150 ml of acetonitrile were heated at 80° C. for 10 days. The reaction was monitored by TLC. Additional disodium hydrogen phosphate was added to maintain the reaction mixture at pH 8. The reaction mixture was cooled and solvent evaporated and the resultant residue was extracted with ethyl acetate (3×), washed with 1M HCl (2×) and brine (2×). The solution was dried over sodium sulfate, filtered and evaporated. The residue which is an isomeric mixture was recrystallized from petroleum ether and gave 2.0 gm 6-chloro-2,3-dimethoxy-1-acetyloxy-4-hydroxynaphthalene, m.p. 155°-6° C.
Reaction SMILES: BrBr.Br[CH:4]([C:16]([C:18]1[N:19]([CH3:23])[CH:20]=[CH:21][CH:22]=1)=[O:17])[CH2:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7].[C:24]([O-:32])(=[S:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Na+]>C(O)(=O)C>[C:24]([S:31][CH:4]([C:16]([C:18]1[N:19]([CH3:23])[CH:20]=[CH:21][CH:22]=1)=[O:17])[CH2:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])(=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: [O-]C(=S)c1ccccc1
Reactant: Cn1cccc1C(=O)C(Br)CC(=O)N1CCC[C@H]1C(=O)O
Agent: BrBr
Agent: [Na+]
Solvent: CC(=O)O
Product: Cn1cccc1C(=O)C(CC(=O)N1CCC[C@H]1C(=O)O)SC(=O)c1ccccc1

Procedure:
As for Example 1, the preceding compound is coupled to L-proline to give 1-[3-(1-methyl-2-pyrrolylcarbonyl)propionyl]-L-proline. The preceding compound (0.01 mole) is brominated with bromine (0.011 mole) in acetic acid and the resulting 1-[3-bromo-(1-methyl-2-pyrrolylcarbonyl)propionyl]-L-proline (0.01 mole) is reacted with sodium thiobenzoate as for Example 21 to give the product of the Example as a glass.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][C:8](Br)(C)[C:9](OCC=C)=O.N1C=CC=CC=1C1C=CC=CN=1.C(OCC)(=O)C>[Cu]Br.C(#N)C>[CH3:7][CH2:8][CH2:9][CH2:6][O:5][C:1]([CH:2]=[CH2:3])=[O:4]
Reactant: C=CCOC(=O)C(C)(C)Br
Reactant: C=CC(=O)OC
Agent: [Cu]Br
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CC(=O)OCCCC
Temperature: 80 °C

Procedure:
To a 30 mL pyrex tube were added methyl acrylate (5 mL, 4.78 g, 55.5 mmole), allyl 2-methyl-2-bromopropionate(0.354 mL, 460 mg, 2.2 mmole), copper (I) bromide (318 mg, 2.22 mmole), 2,2′-bipyridyl (1.04 g, 6.66 mmole), ethyl acetate (4 mL) and acetonitrile (1 mL). The mixture was degassed by three freeze-pump-thaw cycles and then sealed. The mixture was heated to 80° C. for 3 hours and then after cooling to ambient temperature, the mixture was diluted with ethyl acetate (20 mL). An insoluble precipitate was filtered off and the filtrate was washed twice with dil. ECl and once with NaCl solution. The organic layer was dried over Na2SO4and concentrated under reduced pressure to yield a poly(butyl acrylate) having an alkenyl group at one end and a bromine atom at the other end (3.93 g, 75%). The molecular weight and the molecular weight distribution of the polymer were found to be 2700 and 1.48, respectively, by GPC analysis (based on polystyrene standard). The number of alkenyl groups introduced into the polymer was 0.81 based on 1H NMR analysis.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH2:17])[CH3:16])=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+]>ClCCl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH:17][C:5](=[O:7])[CH3:6])[CH3:16])=[CH:11][CH:10]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N[C@@H](C)c1ccc(Br)cc1
Reaction time: 12 h

Procedure:
23.6 mL (250 mmol) acetic anhydride are added to 50.0 g (250 mmol) (S)-1-(4-bromophenyl)-ethylamine in 200 mL dichloromethane while keeping the reaction temperature below 30° C. Stirring is continued for 12 h at rt. After that time, saturated NaHCO3-solution is added. The organic layer is separated, washed with water, dried over magnesium sulphate and the solvent is removed by evaporation.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.O[NH:27][C:28]([C:30]1[S:31][C:32]([S:35](=[O:38])(=[O:37])[NH2:36])=[CH:33][CH:34]=1)=[NH:29]>>[F:25][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:13][N:29]=[C:28]([C:30]4[S:31][C:32]([S:35]([NH2:36])(=[O:38])=[O:37])=[CH:33][CH:34]=4)[N:27]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=2)[CH:4]=1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnn4c(C(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)n2)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) (179 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane) as a yellow solid (200 mg, 74%). MS (EI) 542.0 [(M+H)+]; mp 278° C.